US9623028B2 - Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof - Google Patents

Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof Download PDF

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US9623028B2
US9623028B2 US14/797,548 US201514797548A US9623028B2 US 9623028 B2 US9623028 B2 US 9623028B2 US 201514797548 A US201514797548 A US 201514797548A US 9623028 B2 US9623028 B2 US 9623028B2
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pyrimidin
pyrrolo
ylamino
methoxy
oxazol
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US20160008365A1 (en
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Dan Zhu
John Boylan
Shuichan Xu
Jennifer Riggs
Tao Shi
Andrew WURMSER
David MIKOLON
Gordafaried DEYANAT-YAZDI
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Signal Pharmaceuticals LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • a cancer in particular solid tumors and hematological cancers as described herein, comprising administering an effective amount of a pyrrolopyrimidine compounds to a subject in need thereof.
  • a pyrrolopyrimidine compounds that can be used in said methods.
  • Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis).
  • Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia.
  • the neoplastic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host's immune surveillance (Roitt, I., Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993)).
  • cancer stem cells are resistant to well-defined chemotherapy, and after treatment, they can regenerate all the cell types in the tumor through their stem cell-like behavior of largely quiescent nature and their abundant expression of drug transporters.
  • the Pyrrolopyrimidine Compound provided herein can be used in the methods for treating or preventing the cancer, in particular the solid tumor or the hematological cancer.
  • the methods comprise administering to a subject in need thereof an effective amount of Pyrrolopyrimidine Compound.
  • methods for preventing cancer metastasis comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound as provided herein.
  • the Pyrrolopyrimidine Compound provided herein can be used in the methods for preventing cancer metastasis.
  • a method of eradicating cancer stem cells in a subject comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound as provided herein.
  • the Pyrrolopyrimidine Compound provided herein can be used in the methods of eradicating cancer stem cells in a subject.
  • methods of inducing differentiation in cancer stem cells in a subject comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound as provided herein.
  • the Pyrrolopyrimidine Compound provided herein can be used in the methods of inducing differentiation in cancer stem cells in a subject.
  • the Pyrrolopyrimidine Compound provided herein can be used in the methods of inducing cancer stem cell death in a subject.
  • methods for treating or preventing a cancer, in particular a solid tumor or hematological cancer comprising administering to a subject in need thereof an effective amount of a compound that inhibits TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity.
  • the compound that inhibits TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity can be used in the methods for treating or preventing a cancer, in particular a solid tumor or hematological cancer. Also provided are methods for treating or preventing a cancer associated with the pathways involving TTK, CLK1, and CLK2 and mutants or isoforms thereof, comprising administering to a subject in need thereof an effective amount of a compound that inhibits TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity.
  • the compound that inhibits TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity can be used in the methods for treating or preventing a cancer associated with the pathways involving TTK, CLK1, and CLK2 and mutants or isoforms thereof.
  • the compound that inhibits TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity is a Pyrrolopyrimidine Compound as provided herein.
  • FIG. 1 Pyrrolopyrimidine Compounds showed anti-proliferative activity in a variety of solid tumors, namely, cancers of the bladder, breast, CNS, colon, endocrine, female GU, head and neck, kidney, liver, lung, pancreas, prostate, skin and soft-tissue (exemplified by Cmpd. 38 in FIG. 1 ).
  • FIG. 2 Pyrrolopyrimidine Compounds showed anti-proliferative activity in a variety of hematological cancers, namely, a variety of lymphomas (ST486, CRO-AP2, Faji, MHH-PREB-1, BC-1, DOHH-2, DB, SR, RamosRA1, Daudi, HT, EB-3, SKO-007) and leukemias MOLT-16, BV-173, J-RT3-T3-5, Jurkat, NALM-6, MX1, ARH-77, CML-T1, CCRF-CEM, MV-4-11, EM-2, MOLT-3, CEM-C1, HEL-92-1-7, MEG-01, K-562, THP-1)/myeloma (RPMI-8226, U266B1) (exemplified by Cmpd. 38 in FIG. 2 ).
  • lymphomas ST486, CRO-AP2, Faji, MHH-PREB-1, BC-1, DOHH-2, DB, SR, Ramos
  • FIG. 3 Pyrrolopyrimidine Compounds demonstrated potency against several mesenchymal GBM CSCs (8311, 32612, 81611) with IC 50 s in the range of 1-2 ⁇ M.
  • FIG. 4 Induction of GBM-CSC differentiation by Pyrrolopyrimidine Compounds (for example, Cmpd. 38) is shown in FIG. 4 (left panel: DMSO, right panel: Cmpd. 38).
  • DMSO dimethyl sulfoxide
  • Oct4 octamer-binding transcription factor 4
  • Tuj1 tubulin ⁇ 3
  • DAPI 4′,6-diamidino-2-phenylindole.
  • the 8311 GBM CSCs and HUAEC cells were allowed to co-culture for 1 day prior to compound administration. After 3 days of compound or mock/DMSO-treatment, cells were fixed and monitored for expression of Oct4 and Tuj1 by indirect immunofluorescence.
  • Pyrrolopyrimidine Compounds (exemplified by Cmpd. 38) induced differentiation of GBM CSCs in the context of a HUAEC co-culture model.
  • alkyl group is a saturated, partially saturated, or unsaturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms, typically from 1 to 8 carbons or, in some embodiments, from 1 to 6, 1 to 4, or 2 to 6 or 2 to 4 carbon atoms.
  • Representative alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl and the like.
  • unsaturated alkyl groups include, but are not limited to, vinyl, allyl, —CH ⁇ CH(CH 3 ), —CH ⁇ C(CH 3 ) 2 , —C(CH 3 ) ⁇ CH 2 , —C(CH 3 ) ⁇ CH(CH 3 ), —C(CH 2 CH 3 ) ⁇ CH 2 , —C ⁇ CH, —C ⁇ C(CH 3 ), —C ⁇ C(CH 2 CH 3 ), —CH 2 C ⁇ CH, —CH 2 C ⁇ C(CH 3 ) and —CH 2 C ⁇ C(CH 2 CH 3 ), among others.
  • An alkyl group can be substituted or unsubstituted.
  • alkyl groups described herein When the alkyl groups described herein are said to be “substituted,” they may be substituted with any substituent or substituents as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydra
  • a “cycloalkyl” group is a saturated, or partially saturated cyclic alkyl group of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed or bridged rings which can be optionally substituted with from 1 to 3 alkyl groups.
  • the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl and the like.
  • Examples of unsaturared cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, among others.
  • a cycloalkyl group can be substituted or unsubstituted.
  • Such substituted cycloalkyl groups include, by way of example, cyclohexanol and the like.
  • aryl group is an aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms in the ring portions of the groups. Particular aryls include phenyl, biphenyl, naphthyl and the like. An aryl group can be substituted or unsubstituted.
  • aryl groups also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).
  • heteroaryl group is an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms.
  • heteroaryl groups contain 3 to 6 ring atoms, and in others from 6 to 9 or even 6 to 10 atoms in the ring portions of the groups. Suitable heteroatoms include oxygen, sulfur and nitrogen.
  • the heteroaryl ring system is monocyclic or bicyclic.
  • Non-limiting examples include but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridyl
  • heterocyclyl is an aromatic (also referred to as heteroaryl) or non-aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S and N.
  • heterocyclyl groups include 3 to 10 ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members.
  • Heterocyclyls can also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring).
  • a heterocycloalkyl group can be substituted or unsubstituted.
  • Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl) groups.
  • heterocyclyl includes fused ring species, including those comprising fused aromatic and non-aromatic groups, such as, for example, 1- and 2-aminotetraline, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl.
  • the phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
  • heterocyclyl group examples include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazol
  • benzimidazolyl e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl
  • benzofuranyl benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl (for example, 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl (e.g., azabenzimidazolyl or
  • non-aromatic heterocyclyl groups do not include fused ring species that comprise a fused aromatic group.
  • non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]de
  • substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed below.
  • a “cycloalkylalkyl” group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl, or both the alkyl and the cycloalkyl portions of the group.
  • Representative cycloalkylalkyl groups include but are not limited to methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, propylcyclopentyl, propylcyclohexyl and the like.
  • aralkyl group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are defined above. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • heterocyclylalkyl is a radical of the formula: -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl, or both the alkyl and the heterocyclyl portions of the group.
  • Representative heterocylylalkyl groups include but are not limited to 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyridin-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • a “halogen” is chloro, iodo, bromo, or fluoro.
  • a “hydroxyalkyl” group is an alkyl group as described above substituted with one or more hydroxy groups.
  • alkoxy is —O-(alkyl), wherein alkyl is defined above.
  • alkoxyalkyl is -(alkyl)-O-(alkyl), wherein alkyl is defined above.
  • An “amine” group is a radical of the formula: —NH 2 .
  • a “hydroxyl amine” group is a radical of the formula: —N(R # )OH or —NHOH, wherein R # is a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl group as defined herein.
  • alkoxyamine is a radical of the formula: —N(R # )O-alkyl or —NHO-alkyl, wherein R # is as defined above.
  • an “aralkoxyamine” group is a radical of the formula: —N(R # )O-aryl or —NHO-aryl, wherein R # is as defined above.
  • alkylamine is a radical of the formula: —NH-alkyl or —N(alkyl) 2 , wherein each alkyl is independently as defined above.
  • aminocarbonyl is a radical of the formula: —C( ⁇ O)N(R # ) 2 , —C( ⁇ O)NH(R # ) or —C( ⁇ O)NH 2 , wherein each R # is as defined above.
  • acylamino is a radical of the formula: —NHC( ⁇ O)(R # ) or —N(alkyl)C( ⁇ O)(R # ), wherein each alkyl and R # are independently as defined above.
  • An “O(alkyl)aminocarbonyl” group is a radical of the formula: —O(alkyl)C( ⁇ O)N(R # ) 2 , —O(alkyl)C( ⁇ O)NH(R # ) or —O(alkyl)C( ⁇ O)NH 2 , wherein each R # is independently as defined above.
  • N-oxide group is a radical of the formula: —N + —O ⁇ .
  • a “carboxy” group is a radical of the formula: —C( ⁇ O)OH.
  • a “ketone” group is a radical of the formula: —C( ⁇ O)(R # ), wherein R # is as defined above.
  • aldehyde is a radical of the formula: —CH( ⁇ O).
  • ester is a radical of the formula: —C( ⁇ O)O(R # ) or —OC( ⁇ O)(R # ), wherein R # is as defined above.
  • a “urea” group is a radical of the formula: —N(alkyl)C( ⁇ O)N(R # ) 2 , —N(alkyl)C( ⁇ O)NH(R # ), —N(alkyl)C( ⁇ O)NH 2 , —NHC( ⁇ O)N(R # ) 2 , —NHC( ⁇ O)NH(R # ), or —NHC( ⁇ O)NH 2 # , wherein each alkyl and R # are independently as defined above.
  • An “imine” group is a radical of the formula: —N ⁇ C(R # ) 2 or —C(R # ) ⁇ N(R # ), wherein each R # is independently as defined above.
  • An “imide” group is a radical of the formula: —C( ⁇ O)N(R#)C( ⁇ O)(R # ) or —N((C ⁇ O)(R # ) 2 , wherein each R # is independently as defined above.
  • a “urethane” group is a radical of the formula: —OC( ⁇ O)N(R # ) 2 , —OC( ⁇ O)NH(R # ), —N(R # )C( ⁇ O)O(R # ), or —NHC( ⁇ O)O(R # ), wherein each R # is independently as defined above.
  • An “amidine” group is a radical of the formula: —C( ⁇ N(R # ))N(R # ) 2 , —C( ⁇ N(R # ))NH(R # ), —C( ⁇ N(R # ))NH 2 , —C( ⁇ NH)N(R # ) 2 , —C( ⁇ NH)NH(R # ), —C( ⁇ NH)NH 2 , —N ⁇ C(R # )N(R # ) 2 , —N ⁇ C(R # )NH(R # ), —N ⁇ C(R # )NH 2 , —N(R # )C(R # ) ⁇ N(R # ), —NHC(R # ) ⁇ N(R # ), —N(R # )C(R # ) ⁇ NH, or —NHC(R # ) ⁇ NH, wherein each R # is independently as defined above.
  • a “guanidine” group is a radical of the formula: —N(R # )C( ⁇ N(R # ))N(R # ) 2 , —NHC( ⁇ N(R # ))N(R # ) 2 , —N(R # )C( ⁇ NH)N(R # ) 2 , —N(R # )C( ⁇ N(R # ))NH(R # ), —N(R # )C( ⁇ N(R # ))NH 2 , —NHC( ⁇ NH)N(R # ) 2 , —NHC( ⁇ N(R # ))NH(R # ), —NHC( ⁇ N(R # ))NH 2 , —NHC( ⁇ NH)NH(R # ), —NHC( ⁇ NH)NH 2 , —NHC( ⁇ NH)NH(R # ), —NHC( ⁇ NH)NH 2 , —N ⁇ C(N(R # ) 2 ) 2
  • a “enamine” group is a radical of the formula: —N(R # )C(R # ) ⁇ C(R # ) 2 , —NHC(R # ) ⁇ C(R # ) 2 , —C(N(R # ) 2 ) ⁇ C(R # ) 2 , —C(NH(R # )) ⁇ C(R # ) 2 , —C(NH 2 ) ⁇ C(R # ) 2 , —C(R # ) ⁇ C(R # )(N(R # ) 2 ), —C(R # ) ⁇ C(R # )(NH(R # )) or —C(R # ) ⁇ C(R # )(NH 2 ), wherein each R # is independently as defined above.
  • An “oxime” group is a radical of the formula: —C( ⁇ NO(R # ))(R # ), —C( ⁇ NOH)(R # ), —CH( ⁇ NO(R # )), or —CH( ⁇ NOH), wherein each R # is independently as defined above.
  • a “hydrazide” group is a radical of the formula: —C( ⁇ O)N(R # )N(R # ) 2 , —C( ⁇ O)NHN(R # ) 2 , —C( ⁇ O)N(R # )NH(R # ), —C( ⁇ O)N(R # )NH 2 , —C( ⁇ O)NHNH(R # ) 2 , or —C( ⁇ O)NHNH 2 , wherein each R # is independently as defined above.
  • a “hydrazine” group is a radical of the formula: —N(R # )N(R # ) 2 , —NHN(R # ) 2 , —N(R # )NH(R # ), —N(R # )NH 2 , —NHNH(R # ) 2 , or —NHNH 2 , wherein each R # is independently as defined above.
  • a “hydrazone” group is a radical of the formula: —C( ⁇ N—N(R # ) 2 )(R # ) 2 , —C( ⁇ N—NH(R # ))(R # ) 2 , —C( ⁇ N—NH 2 )(R # ) 2 , —N(R # )(N ⁇ C(R # ) 2 ), or —NH(N ⁇ C(R # ) 2 ), wherein each R # is independently as defined above.
  • An “azide” group is a radical of the formula: —N 3 .
  • An “isocyanate” group is a radical of the formula: —N ⁇ C ⁇ O.
  • An “isothiocyanate” group is a radical of the formula: —N ⁇ C ⁇ S.
  • a “cyanate” group is a radical of the formula: —OCN.
  • a “thiocyanate” group is a radical of the formula: —SCN.
  • a “thioether” group is a radical of the formula; —S(R # ), wherein R # is as defined above.
  • a “thiocarbonyl” group is a radical of the formula: —C( ⁇ S)(R # ), wherein R # is as defined above.
  • a “sulfinyl” group is a radical of the formula: —S( ⁇ O)(R # ), wherein R # is as defined above.
  • a “sulfone” group is a radical of the formula: —S( ⁇ O) 2 (R # ), wherein R # is as defined above.
  • a “sulfonylamino” group is a radical of the formula: —NHSO 2 (R # ) or —N(alkyl)SO 2 (R # ), wherein each alkyl and R # are defined above.
  • a “sulfonamide” group is a radical of the formula: —S( ⁇ O) 2 N(R # ) 2 , or —S( ⁇ O) 2 NH(R # ), or —S( ⁇ O) 2 NH 2 , wherein each R # is independently as defined above.
  • a “phosphonate” group is a radical of the formula: —P( ⁇ O)(O(R # )) 2 , —P( ⁇ O)(OH) 2 , —OP( ⁇ O)(O(R # ))(R # ), or —OP( ⁇ O)(OH)(R # ), wherein each R # is independently as defined above.
  • a “phosphine” group is a radical of the formula: —P(R # ) 2 , wherein each R # is independently as defined above.
  • substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amine; alkylamine; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide
  • Pyrrolopyrimidine Compound refers to compounds of formula (I), as well as to further embodiments provided herein.
  • a “Pyrrolopyrimidine Compound” is a compound set forth in Table 1.
  • the term “Pyrrolopyrimidine Compound” includes pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers and isotopologues of the compounds provided herein.
  • the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base.
  • Suitable pharmaceutically acceptable base addition salts of the compounds of formula (I) include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine.
  • Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.
  • inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic
  • Non-toxic acids include hydrochloric, hydrobromic, maleic, phosphoric, sulfuric, and methanesulfonic acids.
  • Examples of specific salts thus include hydrochloride and mesylate salts.
  • Others are well-known in the art, see for example, Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton Pa. (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton Pa. (1995).
  • stereoisomer or “stereomerically pure” means one stereoisomer of a Pyrrolopyrimidine Compound that is substantially free of other stereoisomers of that compound.
  • a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • the Pyrrolopyrimidine Compounds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.
  • the Pyrrolopyrimidine Compounds can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof.
  • the Pyrrolopyrimidine Compounds are isolated as either the E or Z isomer. In other embodiments, the Pyrrolopyrimidine Compounds are a mixture of the E and Z isomers.
  • Tautomers refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
  • the Pyrrolopyrimidine Compounds can contain unnatural proportions of atomic isotopes at one or more of the atoms.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) sulfur-35 ( 35 S), or carbon-14 ( 14 C), or may be isotopically enriched, such as with deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15 ( 15 N).
  • an “isotopologue” is an isotopically enriched compound.
  • the term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom.
  • “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.
  • the term “isotopic composition” refers to the amount of each isotope present for a given atom.
  • Radiolabeled and isotopically encriched compounds are useful as therapeutic agents, e.g., breast cancer therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the Pyrrolopyrimidine Compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, there are provided isotopologues of the Pyrrolopyrimidine Compounds, for example, the isotopologues are deuterium, carbon-13, or nitrogen-15 enriched Pyrrolopyrimidine Compounds.
  • Treating means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • the disorder is a cancer, in particular, a solid tumor or hematological cancer.
  • “treating” means an alleviation, in whole or in part, of a cancer, or symptoms associated with a cancer, in particular, a solid tumor or hematological cancer, or a slowing, or halting of further progression or worsening of those symptoms.
  • Preventing means a method of delaying and/or precluding the onset, recurrence or spread, in whole or in part, of a cancer, in particular, a solid tumor or hematological cancer; barring a subject from acquiring a cancer, in particular, a solid tumor or hematological cancer; or reducing a subject's risk of acquiring a cancer, in particular, a solid tumor or hematological cancer.
  • the term “effective amount” in connection with a Pyrrolopyrimidine Compound means an amount capable of treating or preventing cancer, in particular, a solid tumor or hematological cancer, or symptoms thereof, as disclosed herein.
  • the effective amount of Pyrrolopyrimidine Compound for example in a pharmaceutical composition, may be at a level that will exercise the desired effect; for example, about 0.005 mg/kg of a subject's body weight to about 100 mg/kg of a patient's body weight in unit dosage for parenteral administration.
  • the effective amount of a Pyrrolopyrimidine Compound disclosed herein may vary depending on the severity of the indication being treated.
  • a subject includes an animal, including, but not limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human.
  • a subject is a human having or at risk for having cancer, in particular, a solid tumor or hematological cancer, or symptoms thereof.
  • a patient is a human having histologically or cytologically-confirmed solid tumor or hematological cancer, including subjects who have progressed on (or not been able to tolerate) standard anticancer therapy or for whom no standard anticancer therapy exists.
  • cancer refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include solid tumors and hematological cancer. In some embodiments, the cancer is a primary cancer, in others, the cancer is metastasized.
  • solid tumors includes, but is not limited to, bladder cancer (including, but not limited to, superficial bladder cancer), breast cancer (including, but not limited to, luminal B type, ER+, PR+ and Her2+ breast cancer), central nervous system cancer (including, but no tlimited to, glioblastoma multiforme (GBM), glioma, medulloblastoma, and astrocytoma), colorectal cancer, gastrointestinal cancer (including, but not limited to, stomach cancer, oesophagus cancer, and rectum cancer), endocrine cancer (including, but not imited to, thyroid cancer, and adrenal gland cancer), eye cancer (including, but not limited to, retinoblastoma), female genitourinary cancer (including, but not limited to, cancer of the placenta, uterus, vulva, ovary, cervix), head and neck cancer (including, but not limited to, cancer of the pharynx, oesophagus
  • the solid tumor is not triple negative breast cancer (TNBC).
  • TNBC triple negative breast cancer
  • the solid tumor is breast cancer, colon cancer, lung cancer or bladder cancer.
  • the solid tumor is superficial bladder cancer.
  • the solid tumor is lung squamous cell carcinoma.
  • the solid tumor is luminal B type breast cancer.
  • hematological cancer includes, but is not limited to, leukemia (including, but not limited to, acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), acute T-cell leukemia, B cell precursor leukemia, acute promyelocytic leukemia (APML), plasma cell leukemia, myelomonoblastic/T-ALL, B myelomonocytic leukemia, erythroleukemia, and acute myeloid leukemia (AML)), lymphoma (including but not limited to Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), B cell lymphoma, lymphoblastic lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), large cell immunoblastic lymphoma), and multiple myeloma.
  • ALL acute lymphocytic leukemia
  • CML
  • inhibition may be assessed by inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor-related symptoms, inhibition of tumor secreted factors (including tumor secreted hormones, such as those that contribute to carcinoid syndrome), delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), increased Overall Survival (OS), among others.
  • OS as used herein means the time from randomization until death from any cause, and is measured in the intent-to-treat population.
  • TTP as used herein means the time from randomization until objective tumor progression; TTP does not include deaths.
  • PFS means the time from randomization until objective tumor progression or death.
  • PFS rates will be computed using the Kaplan-Meier estimates.
  • complete inhibition is referred to herein as prevention or chemoprevention.
  • prevention includes either preventing the onset of clinically evident cancer altogether or preventing the onset of a preclinically evident stage of a cancer.
  • the treatment of lymphoma may be assessed by the International Workshop Criteria (IWC) for non-Hodgkin lymphoma (NHL) (see Cheson B D, Pfistner B, Juweid, M E, et. al. Revised Response Criteria for Malignant Lymphoma. J. Clin. Oncol: 2007: (25) 579-586), using the response and endpoint definitions shown below:
  • IWC International Workshop Criteria
  • NHS non-Hodgkin lymphoma
  • CR complete remission
  • FDG [ 18 F]fluorodeoxyglucose
  • PET positron emission tomography
  • CT computed tomography
  • PR partial remission
  • SPD sum of the product of the diameters
  • SD stable disease
  • PD progressive disease.
  • the end point for lymphoma is evidence of clinical benefit.
  • Clinical benefit may reflect improvement in quality of life, or reduction in patient symptoms, transfusion requirements, frequent infections, or other parameters. Time to reappearance or progression of lymphoma-related symptoms can also be used in this end point.
  • the treatment of CLL may be assessed by the International Workshop Guidelines for CLL (see Hallek M, Cheson B D, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood, 2008; (111) 12: 5446-5456) using the response and endpoint definitions shown therein and in particular:
  • Group A criteria define the tumor load
  • Group B criteria define the function of the hematopoietic system (or marrow).
  • CR complete remission
  • PR partial remission
  • SD absence of progressive disease (PD) and failure to achieve at least a PR
  • PD at least one of the above criteria of group A or group B has to be met.
  • the treatment of multiple myeloma may be assessed by the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie B G M, Harousseau J-L, Miguel J S, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006; (10) 10: 1-7), using the response and endpoint definitions shown below:
  • IURC International Uniform Response Criteria for Multiple Myeloma
  • CR complete response
  • FLC free light chain
  • PR partial response
  • SD stable disease
  • sCR stringent complete response
  • VGPR very good partial response
  • a All response categories require two consecutive assessments made at anytime before the institution of any new therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements; b Confirmation with repeat bone marrow biopsy not needed; c Presence/absence of clonal cells is based upon the ⁇ / ⁇ ratio. An abnormal ⁇ / ⁇ ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis.
  • An abnormal ratio reflecting presence of an abnormal clone is ⁇ / ⁇ of >4:1 or ⁇ 1:2.
  • d Measurable disease defined by at least one of the following measurements: Bone marrow plasma cells ⁇ 30%; Serum M-protein ⁇ 1 g/dl ( ⁇ 10 gm/l)[10 g/l]; Urine M-protein ⁇ 200 mg/24 h; Serum FLC assay: Involved FLC level ⁇ 10 mg/dl ( ⁇ 100 mg/l); provided serum FLC ratio is abnormal.
  • the treatment of a cancer may be assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (see Thereasse P., et al. New Guidelines to Evaluate the Response to Treatment in Solid Tumors. J. of the National Cancer Institute; 2000; (92) 205-216 and Eisenhauer E. A., Therasse P., Bogaerts J., et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European J. Cancer; 2009; (45) 228-247). Overall responses for all possible combinations of tumor responses in target and non-target lesions with our without the appearance of new lesions are as follows:
  • complete response is the disappearance of all target lesions
  • partial response is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter
  • progressive disease is at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions
  • stable disease is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started.
  • complete response is the disappearance of all non-target lesions and normalization of tumor marker level
  • incomplete response/stable disease is the persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits
  • progressive disease is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
  • the procedures, conventions, and definitions described below provide guidance for implementing the recommendations from the Response Assessment for Neuro-Oncology (RANO) Working Group regarding response criteria for high-grade gliomas (Wen P., Macdonald, D R., Reardon, D A., et al. Updated response assessment criteria for highgrade gliomas: Response assessment in neuro-oncology working group. J Clin Oncol 2010; 28: 1963-1972).
  • Primary modifications to the RANO criteria for Criteria for Time Point Responses (TPR) can include the addition of operational conventions for defining changes in glucocorticoid dose, and the removal of subjects' clinical deterioration component to focus on objective radiologic assessments.
  • the baseline MRI scan is defined as the assessment performed at the end of the post-surgery rest period, prior to re-initiating compound treatment.
  • the baseline MRI is used as the reference for assessing complete response (CR) and partial response (PR).
  • CR complete response
  • PR partial response
  • the smallest SPD sum of the products of perpendicular diameters obtained either at baseline or at subsequent assessments will be designated the nadir assessment and utilized as the reference for determining progression.
  • subjects receive either no glucocorticoids or are on a stable dose of glucocorticoids.
  • a stable dose is defined as the same daily dose for the 5 consecutive days preceding the MRI scan. If the prescribed glucocorticoid dose is changed in the 5 days before the baseline scan, a new baseline scan is required with glucocorticoid use meeting the criteria described above. The following definitions will be used.
  • Measurable lesions are contrast-enhancing lesions that can be measured bidimensionally. A measurement is made of the maximal enhancing tumor diameter (also known as the longest diameter, LD). The greatest perpendicular diameter is measured on the same image. The cross hairs of bidimensional measurements should cross and the product of these diameters will be calculated.
  • Minimal Diameter T1-weighted image in which the sections are 5 mm with 1 mm skip.
  • the minimal LD of a measurable lesion is set as 5 mm by 5 mm. Larger diameters may be required for inclusion and/or designation as target lesions. After baseline, target lesions that become smaller than the minimum requirement for measurement or become no longer amenable to bidimensional measurement will be recorded at the default value of 5 mm for each diameter below 5 mm. Lesions that disappear will be recorded as 0 mm by 0 mm.
  • Multicentric Lesions Lesions that are considered multicentric (as opposed to continuous) are lesions where there is normal intervening brain tissue between the two (or more) lesions. For multicentric lesions that are discrete foci of enhancement, the approach is to separately measure each enhancing lesion that meets the inclusion criteria. If there is no normal brain tissue between two (or more) lesions, they will be considered the same lesion.
  • Nonmeasurable Lesions All lesions that do not meet the criteria for measurable disease as defined above will be considered non-measurable lesions, as well as all nonenhancing and other truly nonmeasurable lesions.
  • Nonmeasurable lesions include foci of enhancement that are less than the specified smallest diameter (i.e., less than 5 mm by 5 mm), nonenhancing lesions (e.g., as seen on T1-weighted post-contrast, T2-weighted, or fluid-attenuated inversion recovery (FLAIR) images), hemorrhagic or predominantly cystic or necrotic lesions, and leptomeningeal tumor.
  • FLAIR fluid-attenuated inversion recovery
  • Hemorrhagic lesions often have intrinsic T1-weighted hyperintensity that could be misinterpreted as enhancing tumor, and for this reason, the pre-contrast T1-weighted image may be examined to exclude baseline or interval sub-acute hemorrhage.
  • Target lesions Up to 5 measurable lesions can be selected as target lesions with each measuring at least 10 mm by 5 mm, representative of the subject's disease; Non-target lesions: All other lesions, including all nonmeasurable lesions (including mass effects and T2/FLAIR findings) and any measurable lesion not selected as a target lesion.
  • target lesions are to be measured as described in the definition for measurable lesions and the SPD of all target lesions is to be determined. The presence of all other lesions is to be documented.
  • the baseline classification of lesions as target and non-target lesions will be maintained and lesions will be documented and described in a consistent fashion over time (e.g., recorded in the same order on source documents and eCRFs). All measurable and nonmeasurable lesions must be assessed using the same technique as at baseline (e.g., subjects should be imaged on the same MRI scanner or at least with the same magnet strength) for the duration of the study to reduce difficulties in interpreting changes.
  • target lesions will be measured and the SPD calculated.
  • Non-target lesions will be assessed qualitatively and new lesions, if any, will be documented separately.
  • a time point response will be determined for target lesions, non-target lesions, and new lesion. Tumor progression can be established even if only a subset of lesions is assessed. However, unless progression is observed, objective status (stable disease, PR or CR) can only be determined when all lesions are assessed.
  • TTK (also known as Mps1, hMps1 or PYT) is a dual specificity protein kinase with the ability to phosphorylate tyrosine, serine and threonine. Associated with cell proliferation, this protein is essential for chromosome alignment at the centromere during mitosis and is required for centrosome duplication. It has been found to be a critical mitotic checkpoint protein for accurate segregation of chromosomes during mitosis. Tumorigenesis may occur when this protein fails to degrade and produces excess centrosomes resulting in aberrant mitotic spindles. Alternative splicing results in multiple transcript variants. [RefSeq, November 2009]. TTK is essential for spindle checkpoint function and its inhibition accelerates cell progression through mitosis. TTK also plays an important role for cancer stem cell survival.
  • CLK1 is a member of the CDC2-like (or LAMMER) family of dual specificity protein kinases.
  • the encoded protein phosphorylates serine/arginine-rich (SR) proteins involved in pre-mRNA processing, releasing them into the nucleoplasm.
  • SR serine/arginine-rich
  • the choice of splice sites during pre-mRNA processing may be regulated by the concentration and localization of splicing factors, including serine/arginine rich (SR) proteins. Therefore, the encoded protein may play an indirect role in governing splice site selection. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, June 2009]
  • CLK2 is a member of the CLK family of dual specificity protein kinases. CLK family members have been shown to interact with, and phosphorylate, serine/arginine-rich (SR) proteins of the spliceosomal complex, which is a part of the regulatory mechanism that enables the SR proteins to control RNA splicing. This protein kinase is involved in the regulation of several cellular processes and may serve as a link between cell cycle progression, apoptosis, and telomere length regulation [RefSeq, July 2008]. Inhibition of CLK2 changes the expression of protein isoforms, many of which contribute to the oncogenic phenotype.
  • SR serine/arginine-rich
  • CAMKK2 belongs to the serine/threonine-specific protein kinase family, and to the Ca ++ /calmodulin-dependent protein kinase subfamily. This protein plays a role in the calcium/calmodulin-dependent (CaM) kinase cascade by phosphorylating the downstream kinases CaMK1 and CaMK4 [RefSeq, July 2012]. CAMKK2 reportedly plays a role in tumor energy homeostasis.
  • CaM calcium/calmodulin-dependent
  • R 1 is substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclyl;
  • R 2 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 3 is substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl
  • L is NH or O
  • R 3 is not pyridyl.
  • R 1 is substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclyl;
  • R 2 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 3 is substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl
  • L is NH or O
  • R 3 is not pyridyl when L is NH or when R 2 is pyrazolyl;
  • the compound as described herein is not a compound selected from:
  • the compound is not
  • the compound is not N-methyl-N-[trans-3-[[5-(1-methyl-1H-pyrazol-4-yl)-2-[(1-methyl-1Hpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]cyclobutyl]-2-propenamide (also named N-methyl-N-((1r,3r)-3-((5-(1-methyl-1H-pyrazol-4-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)cyclobutyl)acrylamide)
  • the compound is not
  • R 1 is substituted or unsubstituted alkyl, for example, R 1 is substituted or unsubstituted methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl, or 2,2-dimethylpropyl. In some embodiments, R 1 is substituted or unsubstituted methyl, ethyl, isopropyl, sec-butyl, t-butyl, or 2,2-dimethylpropyl.
  • R 1 is alkyl
  • the alkyl is substituted with one or more —OR or —NR 2 , wherein each R is independently —H or substituted or unsubstituted (C 1-4 )alkyl.
  • R 1 is —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , or —CH 2 CH 2 NHCH 3 .
  • R 1 is substituted or unsubstituted C 3-8 cycloalkyl, for example, R 1 is substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • the cycloalkyl is substituted with one or more —CN, halogen, —OR or a substituted or unsubstituted C 1-3 alkyl, wherein each R is independently —H or substituted or unsubstituted (C 1-4 )alkyl.
  • the cycloalkyl is substituted with one or more —CN, —F, —OH, or —CH 3 .
  • R 1 is substituted or unsubstituted non-aromatic heterocyclyl, for example, R 1 is substituted or unsubstituted oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or piperidinyl.
  • R 1 is substituted or unsubstituted C 1-8 alkyl
  • each R′ is independently —CN, halogen, —OR or C 1-3 alkyl
  • R′′ is —H or C 1-3 alkyl
  • n 0-2.
  • R 1 is substituted or unsubstituted methyl, ethyl, isopropyl, sec-butyl, t-butyl, or 2,2-dimethylpropyl,
  • R′ is —CN, —F, —OH, or —CH 3 ;
  • R′′ is —CH 3 ;
  • n 0, 1 or 2;
  • q 0 or 1.
  • R 2 is substituted phenyl.
  • R 2 is phenyl, substituted with one or more substituted or unsubstituted C 1-6 alkyl, halogen, —CN, —OR 5 , —C( ⁇ O)NR 5 2 , —C( ⁇ O) (substituted or unsubstituted heterocyclyl), —C( ⁇ O) (substituted or unsubstituted alkylheterocyclyl), —NHC( ⁇ O)R 5 , —SO 2 NR 5 2 , or substituted or unsubstituted heteroaryl, wherein each R 5 is independently —H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkylheterocyclyl.
  • R 2 is phenyl, substituted with one or more —(C 1-3 alkyl), —(C 1-3 alkyl)NR 2 , —CF 3 , —Cl, —F, —CN, —OCH 3 , —OCF 3 , —C( ⁇ O)NR 2 , —C( ⁇ O)NR (substituted or unsubstituted cycloalkyl), —C( ⁇ O)NR(CH 2 ) 0-2 CR 2 (CH 2 ) 0-2 OR, —C( ⁇ O)NR(CH 2 ) 0-2 CR 2 (CH 2 ) 0-2 NR 2 , —C( ⁇ O)NR(CH 2 ) 0-2 CR 2 (CH 2 ) 0-2 C( ⁇ O)NR 2 , —C( ⁇ O)N (substituted or unsubstituted cycloalkyl)(CH 2 ) 0-2 OR, —C( ⁇ O)N (
  • R 2 is phenyl, substituted with one or more —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 NH 2 , —CF 3 , —Cl, —F, —CN, —OCH 3 , —OCF 3 , —C( ⁇ O)NH 2 , —C( ⁇ O)NHCH 3 , —C( ⁇ O)N(CH 3 ) 2 , —C( ⁇ O)NC(CH 3 ) 3 , —C( ⁇ O)NHCH 2 CH 2 F, —C( ⁇ O)NHCH 2 CHF 2 , —C( ⁇ O)NHCH 2 CF 3 , —C( ⁇ O)NHCH 2 CF 2 CH 3 , —C( ⁇ O)NHCH 2 CF 2 CH 3 , —C( ⁇ O)NHCH 2 CN, —C( ⁇ O)N(CH 3 )CH 2 CN
  • R 2 is phenyl, substituted with one or more —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 NH 2 , —CF 3 , —Cl, —F, —CN, —OCH 3 , —OCF 3 , —C( ⁇ O)NH 2 , —C( ⁇ O)NHCH 3 , —C( ⁇ O)N(CH 3 ) 2 , —C( ⁇ O)NC(CH 3 ) 3 , —C( ⁇ O)NHCH 2 CH 2 F, —C( ⁇ O)NHCH 2 CF 2 CH 3 , —C( ⁇ O)N(CH 3 )CH 2 CN, —C( ⁇ O)N(CH 3 )CH 2 CH 2 CN, —C( ⁇ O)NH-(3-hydroxy-cyclobutyl), —C( ⁇ O)NH-cyclopentyl
  • R 2 is substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted indazolyl or substituted or unsubstituted isoindolinone.
  • R 2 is substituted with one or more halogen, substituted or unsubstituted (C 1-4 )alkyl, —OR, —C( ⁇ O)NR 2 , or substituted or unsubstituted heterocyclyl, wherein each R is independently —H or substituted or unsubstituted (C 1-4 )alkyl.
  • R 2 is pyrazolyl substituted with one or more —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 OCH 3 , —CH 2 C(CH 3 ) 2 OH, or tetrahydropyranyl.
  • R 2 is pyridyl, substituted with one or more —OCH 3 , C( ⁇ O)NHCH 3 , or tetrahydropyranyl.
  • R 2 is indazolyl or isoindolinone, substituted with one or more —CH 3 .
  • R 1 is substituted or unsubstituted C 1-8 alkyl
  • each R′ is independently —OR or C 1-3 alkyl
  • R′′ is —H or C 1-3 alkyl
  • each R is independently —H or substituted or unsubstituted (C 1-4 )alkyl
  • n 0-2.
  • R 3 is substituted or unsubstituted heterocyclyl, for example, substituted or unsubstituted pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, benztriazolyl, indazolyl, indolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzoxazolonyl, benzoxadiazolyl, benzimidazolyl, or quinolyl.
  • the heterocyclyl is substituted with one or more substituents selected from substituted or unsubstituted (C 1-4 )alkyl, halogen, —OR, —CN, —NR 2 , —C( ⁇ O)NR 2 , —NRC( ⁇ O)R, or substituted or unsubstituted triazolyl, wherein each R is independently —H or substituted or unsubstituted (C 1-4 )alkyl.
  • the heterocyclyl is substituted with one or more substituents selected from —CH 3 , —CH(CH 3 ) 2 , —F, —Cl, —OH, —OCH 3 , —OCH 2 CH 3 , —CN, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C( ⁇ O)NH(CH 3 ), —NHC( ⁇ O)CH 3 , or substituted or unsubstituted triazolyl.
  • the pyrazolyl is substituted with one or more —CH 3 , or —Cl.
  • the pyridyl is substituted with one or more —CH 3 , —F, —Cl, —OH, —OCH 3 , —OCH 2 CH 3 , —CN, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C( ⁇ O)NH(CH 3 ), or —NHC( ⁇ O)CH 3 .
  • the benzoxazolyl is substituted with one or more —CH 3 , —CH(CH 3 ) 2 , —F or —OCH 2 CH 3 .
  • R 3 is substituted or unsubstituted aryl, for example, R 3 is substituted or unsubstituted phenyl.
  • the phenyl is substituted with one or more substituents selected from substituted or unsubstituted C 1-4 alkyl, halogen, —CN, —OR, —NR 2 , —NRSO 2 R′, —NR(C ⁇ O)NR 2 , —NR(C ⁇ O)R′, —COOR, —(C ⁇ O)NR 2 , —C( ⁇ NH)NR 2 , —SO 2 R′, or substituted or unsubstituted heteroaryl, wherein each R is independently —H or substituted or unsubstituted (C 1-4 )alkyl, and R′ is C 1-3 alkyl.
  • the phenyl is substituted with one or more substituents selected from —CH 3 , —CH 2 OH, —CH(OH)CH 3 , —C(CH 3 ) 2 OH, —CN, —F, —Cl, —OH, —OCH 3 , —NH 2 , —N(CH 3 ) 2 , —NHSO 2 CH 3 , —NH(C ⁇ O)NH 2 , —NH(C ⁇ O)CH 3 , —COOCH 3 , —(C ⁇ O)NHCH 3 , —C( ⁇ N)NH 2 , —SO 2 CH 3 , substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazolyl, or substituted or unsubstituted imidazolyl.
  • R 1 is substituted or unsubstituted C 1-8 alkyl
  • each R′ is independently —OR or C 1-3 alkyl
  • R′′ is —H or C 1-3 alkyl
  • each R is independently —H or substituted or unsubstituted (C 1-4 )alkyl
  • n 0-2.
  • R 2 is phenyl, substituted with one or more —(C 1-3 alkyl), —(C 1-3 alkyl)NR 2 , —CF 3 , —Cl, —F, —CN, —OCH 3 , —OCF 3 , —C( ⁇ O)NR 2 , —C( ⁇ O)NR (substituted or unsubstituted cycloalkyl), —C( ⁇ O)NR(CH 2 ) 0-2 CR 2 (CH 2 ) 0-2 OR, —C( ⁇ O)NR(CH 2 ) 0-2 CR 2 (CH 2 ) 0-2 NR 2 , —C( ⁇ O)NR(CH 2 ) 0-2 CR 2 (CH 2 ) 0-2 C( ⁇ O)NR 2 , —C( ⁇ O)N (substituted or unsubstituted cycloalkyl)(CH 2 ) 0-2 OR, —C( ⁇ O)N (
  • the compound is selected from Table A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or isotopologue thereof.
  • the solid tumor is bladder cancer (including superficial bladder cancer), breast cancer (including luminal B type, ER+, PR+ and Her2+ breast cancer), central nervous system cancer (including glioblastoma multiforme (GBM), glioma, medulloblastoma, and astrocytoma), colorectal cancer, gastrointestinal cancer (including stomach cancer, oesophagus cancer, and rectum cancer), endocrine cancer (including thyroid cancer, and adrenal gland cancer), eye cancer (including retinoblastoma), female genitourinary cancer (including cancer of the placenta, uterus, vulva, ovary, cervix), head and neck cancer (including cancer of the pharynx, oesophagus, and
  • the solid tumor is breast cancer, colon cancer, lung cancer or bladder cancer. In one such embodiment, the solid tumor is superficial bladder cancer. In another, the solid tumor is lung squamous cell carcinoma. In yet another embodiment, the solid tumor is luminal B type breast cancer.
  • the hematological cancer is leukemia (including acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), acute T-cell leukemia, B cell precursor leukemia, acute promyelocytic leukemia (APML), plasma cell leukemia, myelomonoblastic/T-ALL, B myelomonocytic leukemia, erythroleukemia, and acute myeloid leukemia (AML)), lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), B cell lymphoma, lymphoblastic lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and large cell immunoblastic lymphoma), or multiple myeloma.
  • ALL acute lymphocytic leukemia
  • CML chronic myeloid leukemia
  • APML acute promy
  • the Pyrrolopyrimidine Compound is a compound as described herein, wherein the compound at a concentration of 10 ⁇ M inhibits cancer cell proliferation, for example solid tumor or hematological cancer cell proliferation, as described herein, by at least about 50% or more.
  • the Pyrrolopyrimidine Compounds described herein can be obtained using conventional organic syntheses and commercially available starting materials.
  • the Pyrrolopyrimidine Compounds have utility as pharmaceuticals to treat, prevent or improve cancer in animals or humans. Accordingly, the Pyrrolopyrimidine Compounds provided herein can be used in all the methods as provided herein. Particularly, the Pyrrolopyrimidine Compounds provided herein can be used in the treatment, prevention or improvement of all diseases disorders, or conditions provided herein. Accordingly, provided herein are uses of the Pyrrolopyrimidine Compounds, including the treatment or prevention of those cancers set forth below.
  • the methods provided herein comprise the administration of an effective amount of one or more Pyrrolopyrimidine Compound(s) to a subject in need thereof.
  • a cancer comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound, as described herein.
  • the cancer is a solid tumor or a hematological tumor.
  • the cancer is not triple negative breast cancer (TNBC).
  • the solid tumor is bladder cancer (including superficial bladder cancer), breast cancer (including luminal B type, ER+, PR+ and Her2+ breast cancer), central nervous system cancer (including glioblastoma multiforme (GBM), glioma, medulloblastoma, and astrocytoma), colorectal cancer, gastrointestinal cancer (including stomach cancer, oesophagus cancer, and rectum cancer), endocrine cancer (including thyroid cancer, and adrenal gland cancer), eye cancer (including retinoblastoma), female genitourinary cancer (including cancer of the placenta, uterus, vulva, ovary, cervix), head and neck cancer (including cancer of the pharynx, oesophagus, and tongue), liver cancer, lung cancer (including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), mucoepidermoid, bronchogenic, squamous cell carcinoma (SQCC), and analplastic/
  • the solid tumor is breast cancer, colon cancer, lung cancer or bladder cancer. In one such embodiment, the solid tumor is superficial bladder cancer. In another, the solid tumor is lung squamous cell carcinoma. In yet another embodiment, the solid tumor is luminal B type breast cancer.
  • the hematological cancer is leukemia (including acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), acute T-cell leukemia, B cell precursor leukemia, acute promyelocytic leukemia (APML), plasma cell leukemia, myelomonoblastic/T-ALL, B myelomonocytic leukemia, erythroleukemia, and acute myeloid leukemia (AML)), lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), B cell lymphoma, lymphoblastic lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and large cell immunoblastic lymphoma), or multiple myeloma.
  • ALL acute lymphocytic leukemia
  • CML chronic myeloid leukemia
  • APML acute promy
  • provided herein are methods for preventing cancer metastasis, comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound, as described herein.
  • the cancer is a metastatic cancer, in particular, a metastatic solid tumor or metastatic hematologic cancer, wherein the solid tumor and hematologic cancer is as described herein.
  • provided herein are methods of preventing cancer metastasis, comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound, as described herein.
  • provided herein are methods of eradicating cancer stem cells in a subject, comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound, as described herein.
  • methods of inducing differentiation in cancer stem cells in a subject comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound, as described herein.
  • methods of inducing cancer stem cell death in a subject comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound, as described herein.
  • the cancer is a solid tumor, for example a CNS cancer (e.g. GBM) or breast cancer, or a hematological cancer, such as leukemia.
  • provided herein are methods for treating or preventing a cancer, in particular a solid tumor or a hematological tumor as described herein, comprising administering to a subject in need thereof an effective amount of a compound that inhibits TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity.
  • methods for treating or preventing a cancer, in particular a solid tumor or a hematological tumor as described herein comprising administering to a subject in need thereof an effective amount of a compound that inhibits TTK, CLK1, and CLK2 kinase activity.
  • the TTK, CLK1, and CLK2 kinase activity is inhibited in a cell. In some embodiments, the TTK, CLK1, and CLK2 kinase activity is inhibited in vivo. In some embodiments, the compound that inhibits TTK, CLK1, and CLK2 kinase activity is a Pyrrolopyrimidine Compound as described herein.
  • kits for treating or preventing a cancer associated with the pathways involving TTK, CLK1, and CLK2, and optionally CAMKK2, and mutants or isoforms thereof comprising administering to a subject in need thereof an effective amount of a compound that inhibits TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity.
  • the cancer associated with the TTK, CLK1, and CLK2, and optionally CAMKK2, pathways include a solid tumor or a hematological tumor as described herein.
  • the TTK, CLK1, and CLK2, and optionally CAMKK2, pathway is inhibited in a cell.
  • the TTK, CLK1, and CLK2, and optionally CAMKK2, pathway is inhibited in vivo.
  • the compound that inhibits TTK, CLK1, and CLK2, and optionally CAMKK2, pathway is a Pyrrolopyrimidine Compound as described herein.
  • provided herein are methods for measuring inhibition of TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity, in a patient having a cancer, for example a solid tumor or a hematological tumor as described herein, comprising administering an effective amount of a Pyrrolopyrimidine Compound to said patient, measuring the amount of TTK, CLK1, and CLK2 kinase activity in said patient, and comparing said amount of TTK, CLK1, and CLK2 kinase activity to that of said patient prior to administration of an effective amount of a Pyrrolopyrimidine Compound.
  • less TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity, in said biological sample obtained after administration of said Pyrrolopyrimidine Compound indicates inhibition.
  • the kinase activity is measured using a radioactivity based kinase assay, which measures the incorporation of a radioactively labeled phosphate moiety (for example, 33 P labeled phosphate) into a substrate, for example, a peptide substrate.
  • a radioactively labeled phosphate moiety for example, 33 P labeled phosphate
  • Reduced levels of radioactively labeled phosphate incorporation into the substrate indicates inhibition of kinase activity.
  • the kinase activity is measured using a time-resolved-fluorescence resonance energy transfer (TR-FRET) based kinase assay, which measures loss of fluorescence as a result of substrate phosphorylation, for example, a peptide substrate (see for example Invitrogen Z'-Lyte Assay®). Increased levels of fluorescence indicates inhibition of kinase activity.
  • the kinase activity is measured using a competitive tracer binding assay (for example, Invitrogen Lanthascreen® Eu binding assay), which measures fluorescence as a result of tracer binding (for example ATP site binding). Reduced fluorescence indicates displacement of tracer binding, which indicates inhibition of kinase activity.
  • TR-FRET time-resolved-fluorescence resonance energy transfer
  • the kinase activity is measured using a cellular biomarker assay, which measures the phosphorylation of a substrate, for example a downstream substrate, using Western Blot, ELISA or Mesoscale. Reduced phosphorylation of the substrate indicates inhibition of kinase activity.
  • the inhibition of TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity is assessed in a biological sample of the patient, such as in circulating blood cells, or tumor or skin biopsies.
  • the amount of inhibition of kinase activity is assessed by comparison of the amount of phosphorylated substrate (for example for TTK: phospho-TTK, such as p-TTK T686, or phosphorylated borealin, BubR1, Chk2, c-Abl, p53, Mip1 or TACC2; and for CLK2 (phospho-SRp75, or phosphorylated PP2A regulatory subunit B56 ⁇ (PPP2R5B, B′ ⁇ ) or PGC-1 ⁇ ) before and after administration of the Pyrrolopyrimidine Compound to the patient.
  • TTK phospho-TTK, such as p-TTK T686, or phosphorylated borealin, BubR1, Chk2, c-Abl, p53, Mip1 or TACC2
  • CLK2 phospho-SRp75, or phosphorylated PP2A regulatory subunit B56 ⁇ (PPP2R5B, B′ ⁇ ) or PGC-1 ⁇
  • less phosphorylated TTK substrate and less phosphorylated CLK2 substrate, in said biological sample, obtained after administration of said Pyrrolopyrimidine Compound relative to the amount of phosphorylated TTK substrate and phosphorylated CLK2 substrate, in said biological sample obtained prior to administration of said Pyrrolopyrimidine Compound indicates inhibition.
  • less phospho-TTK (for example p-TTK T686) and phospho-SRp75, in said biological sample obtained after administration of said Pyrrolopyrimidine Compound relative to the amount of phospho-TTK (for example p-TTK T686) and phospho-SRp75, in said biological sample obtained prior to administration of said Pyrrolopyrimidine Compound indicates inhibition.
  • provided herein are methods for inhibiting TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity, in a patient having a cancer, in particular a solid tumor or a hematological tumor as described herein, comprising administering an effective amount of a Pyrrolopyrimidine Compound to said patient.
  • the methods additionally comprise comparing the amount of TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 activity, in a biological sample of a patient obtained prior to and after administration of said Pyrrolopyrimidine Compound, wherein less TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity, in said biological sample obtained after administration of said Pyrrolopyrimidine Compound relative to the amount of TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity, in said biological sample obtained prior to administration of said Pyrrolopyrimidine Compound indicates inhibition.
  • the methods additionally comprise comparing the amount of phosphorylated substrate (for example for TTK: phospho-TTK, such as p-TTK T686, or phosphorylated borealin, BubR1, Chk2, c-Abl, p53, Mip1 or TACC2; and for CLK2 (phospho-SRp75, or phosphorylated PP2A regulatory subunit B56 ⁇ (PPP2R5B, B′ ⁇ ) or PGC-1 ⁇ ) in a biological sample of a patient obtained prior to and after administration of said Pyrrolopyrimidine Compound, wherein less phosphorylated substrate in said biological sample obtained after administration of said Pyrrolopyrimidine Compound relative to the amount of phosphorylated substrate in said biological sample obtained prior to administration of said Pyrrolopyrimidine Compound indicates inhibition.
  • TTK phospho-TTK, such as p-TTK T686, or phosphorylated borealin, BubR1, Chk2, c-Abl, p53, Mip1 or TACC2
  • the methods additionally comprise comparing the amount of phospho-TTK (for example p-TTK T686) and phospho-SRp75, in a biological sample of a patient obtained prior to and after administration of said Pyrrolopyrimidine Compound, wherein less phospho-TTK (for example p-TTK T686) and phospho-SRp75, in said biological sample obtained after administration of said Pyrrolopyrimidine Compound relative to the amount of phospho-TTK (for example p-TTK T686) and phospho-SRp75, in said biological sample obtained prior to administration of said Pyrrolopyrimidine Compound indicates inhibition.
  • phospho-TTK for example p-TTK T686
  • phospho-SRp75 for example phospho-SRp75
  • the TTK kinase activity is inhibited with an IC 50 no greater than about 20 nM. In another, the TTK kinase activity is inhibited with an IC 50 between about 0.01 nM and about 20 nM. In others, the TTK kinase activity is inhibited with an IC 50 between about 0.01 nM and about 100 nM. In still others, the TTK kinase activity is inhibited with an IC 50 between about 0.01 nM and about 200 nM. In yet others, the TTK kinase activity is inhibited with an IC 50 between about 0.1 nM and about 500 nM.
  • the CLK1 kinase activity is inhibited with an IC 50 no greater than about 300 nM. In some embodiments, the CLK1 kinase activity is inhibited with an IC 50 between about 1 nM and about 100 nM. In others, the CLK1 kinase activity is inhibited with an IC 50 between about 1 nM and about 500 nM. In yet others, the CLK1 kinase activity is inhibited with an IC 50 between about 1 nM and about 1000 nM. In some embodiments, the CLK2 kinase activity is inhibited with an IC 50 no greater than about 10 nM.
  • the CLK2 kinase activity is inhibited with an IC 50 between about 0.01 nM and about 20 nM. In others, the CLK2 kinase activity is inhibited with an IC 50 between about 0.01 nM and about 100 nM. In still others, the CLK2 kinase activity is inhibited with an IC 50 between about 0.01 nM and about 200 nM. In yet others, the CLK2 kinase activity is inhibited with an IC 50 between about 0.1 nM and about 500 nM. In some embodiments, the CAMKK2 kinase activity is inhibited with an IC 50 no greater than about 1000 nM.
  • the CAMKK2 kinase activity is inhibited with an IC 50 between about 1 nM and about 500 nM. In others, the CAMKK2 kinase activity is inhibited with an IC 50 between about 1 nM and about 1000 nM. In still others, the CAMKK2 kinase activity is inhibited with an IC 50 between about 1 nM and about 2000 nM. In yet others, the CAMKK2 kinase activity is inhibited with an IC 50 between about 1 nM and about 5000 nM.
  • provided herein are methods for achieving a Response Evaluation Criteria in Solid Tumors (RECIST 1.1) of complete response, partial response or stable disease in a patient comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein.
  • methods to increase Progression Free Survival rates as determined by Kaplan-Meier estimates.
  • provided herein are methods for preventing or delaying a Response Evaluation Criteria in Solid Tumors (RECIST 1.1) of progressive disease in a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a solid tumor as described herein.
  • the prevention or delaying of progressive disease is characterized or achieved by a change in overall size of the target lesions, of for example, between ⁇ 30% and +20% compared to pre-treatment.
  • the change in size of the target lesions is a reduction in overall size of more than 30%, for example, more than 50% reduction in target lesion size compared to pre-treatment.
  • the prevention is characterized or achieved by a reduction in size or a delay in progression of non-target lesions compared to pre-treatment. In one embodiment, the prevention is achieved or characterized by a reduction in the number of target lesions compared to pre-treatment. In another, the prevention is achieved or characterized by a reduction in the number or quality of non-target lesions compared to pre-treatment. In one embodiment, the prevention is achieved or characterized by the absence or the disappearance of target lesions compared to pre-treatment. In another, the prevention is achieved or characterized by the absence or the disappearance of non-target lesions compared to pre-treatment. In another embodiment, the prevention is achieved or characterized by the prevention of new lesions compared to pre-treatment. In yet another embodiment, the prevention is achieved or characterized by the prevention of clinical signs or symptoms of disease progression compared to pre-treatment, such as cancer-related cachexia or increased pain.
  • provided herein are methods for decreasing the size of target lesions in a patient compared to pre-treatment, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein.
  • provided herein are methods for decreasing the size of a non-target lesion in a patient compared to pre-treatment, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein.
  • provided herein are methods for achieving a reduction in the number of target lesions in a patient compared to pre-treatment, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein.
  • provided herein are methods for achieving a reduction in the number of non-target lesions in a patient compared to pre-treatment, comprising administering an effective amount a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein.
  • provided herein are methods for achieving an absence of all target lesions in a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein.
  • provided herein are methods for achieving an absence of all non-target lesions in a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein.
  • provided herein are methods for treating a cancer, in particular a solid tumor as described herein, the methods comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor, wherein the treatment results in a complete response, partial response or stable disease, as determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
  • RECIST 1.1 Response Evaluation Criteria in Solid Tumors
  • provided herein are methods for treating a cancer, in particular a solid tumor as described herein, the methods comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein, wherein the treatment results in a reduction in target lesion size, a reduction in non-target lesion size and/or the absence of new target and/or non-target lesions, compared to pre-treatment.
  • provided herein are methods for treating a cancer, in particular a solid tumor as described herein, the methods comprising administering an effective amount a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein, wherein the treatment results in prevention or retarding of clinical progression, such as cancer-related cachexia or increased pain.
  • kits for inducing a therapeutic response characterized with the International Workshop Criteria (IWC) for NHL comprising administering an effective amount a Pyrrolopyrimidine Compound to a patient having a cancer, in particular hematological cancers such as lymphoma, as described herein.
  • kits for achieving complete remission, partial remission or stable disease as determined by the International Workshop Criteria (IWC) for NHL in a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular hematological cancers such as lymphoma, as described herein.
  • IWC International Workshop Criteria
  • kits for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, disease-free survival or lymphoma-free survival as determined by the International Workshop Criteria (IWC) for NHL in a patient comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular hematological cancers such as lymphoma, as described herein.
  • IWC International Workshop Criteria
  • IURC International Uniform Response Criteria for Multiple Myeloma
  • methods for inducing a therapeutic response assessed with the International Uniform Response Criteria for Multiple Myeloma assessed with the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie B G M, Harousseau J-L, Miguel J S, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006; (10) 10: 1-7) of a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular multiple myeloma.
  • IURC International Uniform Response Criteria for Multiple Myeloma
  • provided herein are methods for achieving a stringent complete response, complete response, or very good partial response, as determined by the International Uniform Response Criteria for Multiple Myeloma (IURC) in a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular multiple myeloma.
  • IURC International Uniform Response Criteria for Multiple Myeloma
  • methods for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular multiple myeloma.
  • RANO Neuro-Oncology
  • GBM glioblastoma multiforme
  • ECOG Eastern Cooperative Oncology Group Performance Status
  • provided herein are methods for inducing a therapeutic response assessed by Positron Emission Tomography (PET) outcome of a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor or hematological cancer as described herein.
  • methods for treating a cancer, in particular a solid tumor or hematological cancer as described herein the methods comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor or hematological cancer as described herein, wherein the treatment results in a reduction in tumor metabolic activity, for example, as measured by PET imaging.
  • the Pyrrolopyrimidine Compound is a compound as described herein. In one embodiment, the Pyrrolopyrimidine Compound is a compound of formula (I). In another embodiment, the Pyrrolopyrimidine Compound is a compound from Table A. In one embodiment, the Pyrrolopyrimidine Compound is a Pyrrolopyrimidine Compound set forth herein having molecular formula C 26 H 24 N 6 O 4 . In another, the Pyrrolopyrimidine Compound is a Pyrrolopyrimidine Compound set forth herein having molecular formula C 26 H 26 N 6 O 4 .
  • the Pyrrolopyrimidine Compound is a Pyrrolopyrimidine Compound set forth herein having molecular formula C 26 H 27 N 5 O 4 .
  • the Pyrrolopyrimidine Compound is a Pyrrolopyrimidine Compound set forth herein having molecular formula C 28 H 28 N 6 O 4 .
  • the Pyrrolopyrimidine Compound is a Pyrrolopyrimidine Compound set forth herein having molecular formula C 28 H 30 N 6 O 4 .
  • the Pyrrolopyrimidine Compound is a Pyrrolopyrimidine Compound set forth herein having molecular formula C 29 H 30 N 6 O 5 .
  • the Pyrrolopyrimidine Compound is 4-((4-(cyclopentyloxy)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (Compound 3).
  • the Pyrrolopyrimidine Compound is 4-((4-cyclopropoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (Compound 152).
  • the Pyrolopyrimidine is 4-((4-isopropoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (Compound 125).
  • the Pyrolopyrimidine is 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (Compound 38).
  • the Pyrolopyrimidine is 4-((4-(cyclopentyloxy)-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (Compound 79).
  • the Pyrolopyrimidine is 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-3-methoxybenzamide (Compound 101).
  • a cancer in particular a solid tumor or a hematological cancer as described herein, as well as those who have not previously been treated.
  • the treatment given to a patient may vary, depending on his/her prognosis.
  • the skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based standard therapy that can be effectively used to treat an individual patient with a cancer.
  • the Pyrrolopyrimidine Compounds can be administered to a subject parenterally in the conventional form of preparations, such as injections, suspensions, solutions and emulsions.
  • Suitable vehicles that can be used to provide intravenous formulations of a Pyrrolopyrimidine Compound are well known to those skilled in the art.
  • Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol
  • An intravenous formulation can be prepared by reconstituting a Pyrrolopyrimidine Compound with such a suitable liquid vehicle.
  • a desired concentration of the intravenous formulation can be obtained by reconstituting an appropriate amount of a Pyrrolopyrimidine Compound with an appropriate volume of liquid vehicle.
  • a desired concentration of the intravenous formulation provides a therapeutically effective amount of a Pyrrolopyrimidine Compound to the patient in need of the intravenous formulation and maintains a therapeutically effective level of a Pyrrolopyrimidine Compound in the patient.
  • the dose which is therapeutically effective will depend on the rate at which the intravenous formulation is delivered to the patient and the concentration of the intravenous formulation.
  • the effective amount of the Pyrrolopyrimidine Compound in the pharmaceutical composition may be at a level that will exercise the desired effect; for example, about 0.005 mg/kg of a subject's body weight to about 100 mg/kg of a subject's body weight in unit dosage for parenteral administration.
  • the dose of a Pyrrolopyrimidine Compound to be administered to a subject is rather widely variable and can be subject to the judgment of a health-care practitioner.
  • the Pyrrolopyrimidine Compounds can be administered one to seven times a week, once every two weeks, once every three weeks or once every four weeks in a dose of about 0.005 mg/kg of a subject's body weight to about 10 mg/kg of a subject's body weight in a subject, but the above dosage may be properly varied depending on the age, body weight and medical condition of the subject and the type of administration.
  • the dose is about 0.01 mg/kg of a subject's body weight to about 5 mg/kg of a subject's body weight, about 0.05 mg/kg of a subject's body weight to about 1 mg/kg of a subject's body weight, about 0.1 mg/kg of a subject's body weight to about 0.75 mg/kg of a subject's body weight or about 0.25 mg/kg of a subject's body weight to about 0.5 mg/kg of a subject's body weight.
  • one dose is given per week. In others, one dose is given two, three or four times per week. In still others, one dose is given per two weeks, per three weeks or per four weeks. In any given case, the amount of the Pyrrolopyrimidine Compound administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.
  • kits for the treatment or prevention of a disease or disorder comprising the administration of about 0.375 mg/dose to about 750 mg/dose, about 0.75 mg/dose to about 375 mg/dose, about 3.75 mg/dose to about 75 mg/dose, about 7.5 mg/dose to about 55 mg/dose or about 18 mg/dose to about 37 mg/dose of a Pyrrolopyrimidine Compound to a subject in need thereof.
  • kits for the treatment or prevention of a disease or disorder comprising the administration of about 1 mg/dose to about 1200 mg/dose, about 10 mg/dose to about 1200 mg/dose, about 100 mg/dose to about 1200 mg/dose, about 400 mg/dose to about 1200 mg/dose, about 600 mg/dose to about 1200 mg/dose, about 400 mg/dose to about 800 mg/dose or about 600 mg/dose to about 800 mg/dose of a Pyrrolopyrimidine Compound to a subject in need thereof.
  • the methods disclosed herein comprise the administration of 400 mg/dose, 600 mg/dose or 800 mg/dose of a Pyrrolopyrimidine Compound to a subject in need thereof.
  • unit dosage formulations that comprise between about 1 mg and 200 mg, about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, or about 500 mg and about 1000 mg of a Pyrrolopyrimidine Compound.
  • unit dosage formulations comprising about 100 mg or 400 mg of a Pyrrolopyrimidine Compound.
  • unit dosage formulations that comprise 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a Pyrrolopyrimidine Compound.
  • a Pyrrolopyrimidine Compound can be administered once, twice, three, four or more times daily.
  • doses of 600 mg or less are administered as a once daily dose and doses of more than 600 mg are administered twice daily in an amount equal to one half of the total daily dose.
  • compositions comprising an effective amount of a Pyrrolopyrimidine Compound and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.
  • a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.
  • the composition is a pharmaceutical composition.
  • compositions can be in the form of solutions, parenteral solutions, and suspensions and the like.
  • Compositions can be formulated to contain a single dose, or a convenient fraction of a single dose, in a dosage unit, which may be a single vial or convenient volume of a liquid.
  • the solutions are prepared from water-soluble salts, such as the hydrochloride salt.
  • all of the compositions are prepared according to known methods in pharmaceutical chemistry.
  • the effect of the Pyrrolopyrimidine Compound can be delayed or prolonged by proper formulation.
  • the parenteral preparations can be made long-acting, by dissolving or suspending the Pyrrolopyrimidine Compound in oily or emulsified vehicles that allow it to disperse slowly in the serum.
  • a fluorescence resonance energy transfer-based Z'-LYTE® kinase assay kit-Ser/Thr 09 was used to determine the IC 50 values for inhibition of CLK1 kinase activity.
  • the reactions were performed in a 384-well plate with a 10 ⁇ l reaction volume per well containing CLK1 enzyme (16.2-128 ng), 25 ⁇ M adenosine triphosphate (ATP), 2 ⁇ M Z'-Lyte® Ser/Thr 9 peptide substrate in 50 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.5, 0.01% Brij-35, 10 mM magnesium chloride (MgCl 2 ), 1 mM ethylene glycol tetraacetic acid (EGTA) buffer with a serial 3-fold dilution of the test compounds.
  • CLK1 enzyme 16.2-128 ng
  • ATP adenosine triphosphate
  • HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
  • pH 7.5 pH 7.5
  • Brij-35 pH 7.5
  • 10 mM magnesium chloride MgCl 2
  • EGTA
  • a fluorescence resonance energy transfer-based Z'-LYTE® kinase assay kit-Ser/Thr 6 peptide (Invitrogen, Carlsbad, Calif., cat.# PV3179) was used to determine the IC 50 values for inhibition of CLK2 kinase activity.
  • the reactions were performed in a 384-well plate with a 10 ⁇ l reaction volume per well containing CLK2 enzyme (ranging from 0.97-11.5 ng), 25 ⁇ M ATP, 2 ⁇ M Z'-Lyte® Ser/Thr 6 peptide substrate in 50 mM HEPES, pH 7.5, 0.01% Brij-35, 10 mM MgCl 2 , 1 mM EGTA buffer with a serial 3-fold dilution of the test compounds. After a 1 hour incubation, 5 ⁇ L of Development Reagent A (1:2048 dilution) was added, and the fluorescence ratio was calculated.
  • the LanthaScreen® Eu Kinase Binding Assay (Invitrogen, Carlsbad, Calif. cat.#) was used to determine the IC 50 values for inhibition of TTK kinase activity.
  • the reaction was performed in a 384-well plate with a 16 ⁇ L reaction volume per well containing 5 nM TTK enzyme, 30 nM of Tracer 236 (Invitrogen PV5592), and 2 nM LanthaScreen® Eu-anti-GST antibody in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl 2 , 1 mM EGTA buffer with a serial 3-fold dilution of test compound.
  • the reaction was incubated for 1 hour at room temperature and then read on a fluoresence plate reader (Excitation 340 nm, Kinase Tracer 236 Emission: 665 nm, LanthaScreenTM Eu-anti-Tag Antibody: Emission 615 nm).
  • the TR-FRET ratio was calculated as the intensity of the acceptor signal (665 nm) divided by the intensity of the donor signal (615 nm).
  • the dose-response curves were fitted to a sigmoidal dose-response model using XLfit from IDBS.
  • the IC 50 values were determined as the concentration of compound resulting in 50% of displaced Tracer 236 (ATP competive inhibitor). Results for certain Pyrrolopyrimidine Compounds are shown in Tables B and C.
  • the LanthaScreen® Eu Kinase Binding Assay (Invitrogen, Carlsbad, Calif.) was used to determine the IC 50 values for inhibition of CAMKK2 kinase activity.
  • the reaction was performed in a 384-well plate with a 16 ⁇ L reaction volume per well containing 5 nM CAMKK2 enzyme, 10 nM of Kinase Tracer 236, and 2 nM LanthaScreen® Eu-anti-GST antibody in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA buffer with a serial 3-fold dilution of test compound.
  • the reaction was incubated for 1 hour at room temperature and then read on a fluoresence plate reader (Excitation 340 nm, Kinase Tracer 236 Emission: 665 nm, and LanthaScreenTM Eu-anti-Tag Antibody: Emission 615 nm).
  • the TR-FRET ratio was calculated as the intensity of the acceptor signal (665 nm) divided by the intensity of the donor signal (615 nm).
  • the dose-response curves were fitted to a sigmoidal dose-response model using XLfit from IDBS.
  • the IC 50 values were determined as the concentration of compound resulting in 50% of displaced Tracer 236 (ATP competive inhibitor).
  • CAMKK2 enzyme was mixed with 1 ⁇ M of Ca 2+ -Calmodulin and 10 ⁇ M of the Mylein Basic Protein (MBP) substrate in reaction buffer; 20 mM 4-(2-hydroxyethyl)-1-piperazineethane sulfonic acid (HEPES), 10 mM magnesium chloride (MgCl 2 ), 1 mM ethyleneglycoltetraacetic acid (EGTA), 0.02% Brij35, 0.02 mg/ml bovine serum albumin (BSA), 0.1 mM sodium orthovanadate, 2 mM dithiothreitol (DTT), 1% dimethyl sulfoxide (DMSO) at pH 7.5.
  • MBP Mylein Basic Protein
  • TTK CLK1 CLK2 CAMKK2 Cmpd No. (IC 50 , ⁇ M) (IC 50 , ⁇ M) (IC 50 , ⁇ M) (IC 50 , ⁇ M) (IC 50 , ⁇ M) 3 1.435624 0.05389 11 0.298738 0.034896 16 0.225404 0.025999 17 0.082369 0.00433 38 0.014 0.267 0.008168 0.728 55 0.013312 67 0.016027 79 0.002379 0.058587 0.001911 0.034 89 ⁇ 1.5e ⁇ 003 0.041473 0.004557 90 0.001675 0.12394 0.003497 101 0.002128 0.099779 0.003377 0.501 118 0.005136 0.002294 132 0.004116 0.225986 0.029057 134 0.001678 0.130033 0.00227 145 0.00
  • Tables B and C show that Pyrrolopyrimidine Compounds, as described herein, inhibit the kinase activity of TTK, CLK1, and CLK2. In some embodiments, the Pyrrolopyrimidine Compounds also inhibit the kinase activity of CAMKK2.
  • the 49 breast cancer cell lines used in the study are shown in Table 1.
  • the luminal and basal subtype classification was based upon public information that was verified internally.
  • the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status of each cell line was based upon public information that was verified internally.
  • ER estrogen receptor
  • FBS fetal bovine serum
  • HER2 human epidermal growth factor receptor 2
  • NCI National Cancer Institute
  • PR progesterone receptor
  • TN triple negative breast cancer: ER ⁇ , PR ⁇ , and HER2 ⁇ .
  • NSCLC non small cell lung cancer
  • the compound vehicle (DMSO) was maintained at a final concentration of 0.2% in all wells. After 72 hrs, 100 ⁇ L of Cell Titer Glo solution (Promega) were added to each well of the 96-well plate. The plate was placed on a shaker for 2 minutes. After 10 minutes incubation, luminescence signal was detected with Envision microplate reader (Perkin Elmer). The IC 50 values were calculated as the concentration of compound at which the level of luminescence signal was reduced to 50% of the signal window. Table 4 shows the results for Compound 3. Compounds show or will show an IC 50 value ranging from 0.01-30 ⁇ M in this assay.
  • Pyrrolopyrimidine Compounds demonstrated potent growth inhibition over a panel of non small cell lung cancer cell (NSCLC) lines profiled, as shown in Table 4.
  • NSCLC non small cell lung cancer cell
  • the majority of NSCLC lines (14 out of 16) are sensitive to growth inhibition by Pyrrolopyrimidine Compounds (for example, Compound 3) with a IC 50 values ⁇ 2 ⁇ M.
  • Cells were grown in RPMI1640, 10% FBS, 2 mM L-alanyl-L-Glutamine, 1 mM Na pyruvate or a special medium in a humidified atmosphere of 5% CO 2 at 37° C. Cells were seeded into 384-well plates and incubated in a humidified atmosphere of 5% CO 2 at 37° C. Compounds were added 24 hours post cell seeding. At the same time, a time zero untreated cell plate was generated. After a 72 hour incubation period, cells were fixed and stained with fluorescently labeled antibodies and nuclear dye to allow visualization of nuclei, apoptotic cells and mitotic cells. Apoptotic cells were detected using an anti-active caspase-3 antibody.
  • Mitotic cells were detected using an anti phospho-histone-3 antibody. Compounds were serially diluted 3.16-fold and assayed over 10 concentrations in a final assay concentration of 0.1% DMSO from the highest test concentration of 10 ⁇ M. Automated fluorescence microscopy was carried out using a GE Healthcare IN Cell Analyzer 1000, and images were collected with a 4 ⁇ objective.
  • Relative cell count IC 50 is the test compound concentration at 50% of maximal possible response relative to the DMSO control.
  • GI 50 is the concentration needed to reduce the observed growth by half. This is the concentration that inhibits the growth to the level midway between growth in untreated cells and the number of cells seeded in the well (Time zero value).
  • the activated caspase-3 marker labels cells from early to late stage apoptosis.
  • the output is shown as a fold increase of apoptotic cells over vehicle background normalized to the relative cell count in each well.
  • Concentrations of test compound that cause a 5-fold induction in the caspase-3 signal (Cal_X5) indicate significant apoptosis induction.
  • the maximal induction of caspase 3 by compound in comparison with DMSO control is reported as Max_Fold_Change.
  • CSCs cancer stem cells
  • HUVECs were plated in 20 ⁇ L per well of a 384-well plate in Endothelial Growth Media Microvascular-2. After 1 day of cultivation, 20 ⁇ L/well of respective fresh medium for each cell type was added and the cells were treated with Pyrrolopyrimidine Compounds at multiple concentrations or 0.04 ⁇ L DMSO for 3 days under 5% CO 2 /37° C. culture conditions. After 3 days of compound treatment, cells were lysed through the addition of 30 ⁇ L of CellTiter-Glo (CTG) reagent to evaluate relative cell density. The plate was placed at room temperature for 30 minutes after which luminescent signal was monitored.
  • CTG CellTiter-Glo
  • Table 7 summarizes the GBM subtype affiliation of each GBM-CSC model utilized.
  • the impact of Pyrrolopyrimidine Compounds on the growth of GBM-CSCs was tested under defined serum-free culture conditions by CTG. The concentration of compound that inhibited the cell growth by 50% was determined in those five models (data for Compound 38 is summarized in FIG. 3 ).
  • Pyrrolopyrimidine Compounds (exemplified by Compound 38) demonstrated potency against mesenchymal GBM CSCs with IC 50 s in the range of 1-2 ⁇ M.
  • GBM-Cancer Stem Cells Patient CSCs Clinical Diagnosis Subtype 8311 GBM Mesenchymal (Mes) 52810 GBM Proneural (PN) 81611 GBM PN/Relapse 32612 GBM Mesenchymal (Mes) 1912 GBM Proneural (PN)
  • 1200 HUAECs were plated per well of a 384-well plate. After 1 day 8311 GBM CSCs were mechanically-dissociated by trituration and added at a density of 600 cells per well. The cells were allowed to co-culture for 1 day and then treated with various concentrations of Pyrrolopyrimidine Compound or DMSO for 3 days in 5% CO 2 at 37° C. After incubation with compound, 40 ⁇ L of 4% paraformaldehyde was added. Cell fixation was allowed to proceed at room temperature for 1 hour and each well was washed 5 times with a 50 ⁇ L volume of PBS. Each well was treated overnight at 4° C.
  • GBM CSCs demonstrated the ability to undergo neuronal and astrocytic differentiation upon growth factor withdrawal or following exposure to BMP-4 [Pollard et at Cell Stem Cell 2009; 4(6):568-80].
  • BMP-4 Polymethyl methacrylate phosphate
  • Endothelial cells are known to interact closely with self-renewal GBM-CSC and secret factors maintaining these cells in stem-cell like state [Calabrese et al. Cancer cell 2007; 11(1):69-82].
  • Oct 4 was used as stem cell marker and Tuj-1 was used as neuronal marker for GBM-CSC and differentiated neuronal cell populations, respectively.
  • Tuj-1 was used as neuronal marker for GBM-CSC and differentiated neuronal cell populations, respectively.
  • FIG. 4 upon Pyrrolopyrimidine Compound treatment (as shown for Compound 38), the Oct4 positive GBM CSC population was decreased while the proportion of Tuj-1 positive neuronal cells was increased. This data indicates that Pyrrolopyrimidine Compounds can eliminate the Oct-4 positive cancer stem cell population and induce neuronal differentiation in the 8311/HUAEC co-culture model.
  • Pyrrolopyrimidine Compounds were shown to impair the proliferation of GBM CSC models. Five models isolated from primary GBM patient specimens, representative of mesenchymal and proneural GBM subclasses, were utilized to test Pyrrolopyrimidine Compound activity upon GBM CSCs. Pyrrolopyrimidine Compounds (as exemplified by Compound 38) potently inhibited proliferation of proneural 52810 and 1912 cells with IC 50 values of 0.048 and 0.19 ⁇ M, respectively. Pyrrolopyrimidine Compounds (exemplified by Compound 38) had less potency in the inhibition of mesenchymal models 8311 and 32612 cells with IC 50 values of 1.6 and 1.8 ⁇ M, respectively.
  • Pyrrolopyrimidine Compounds (exemplified by Compound 38) induced differentiation of GBM CSCs in the context of a HUAEC co-culture model.
  • Pyrrolopyrimidine Compounds can both inhibit proliferation and induce neuronal differentiation of GBM CSCs.
  • mice human cancer cell lines were injected into SCID (severe combined immunodeficiency) mice. Cancer cell lines were propagated in culture in vitro. Tumor bearing animals were generated by injecting precisely determined numbers of cells into mice. Following inoculation of animals, the tumors were allowed to grow to a certain size prior to randomization. The mice bearing xenograft tumors, typically ranging between 100 and 400 mm 3 , were pooled together and randomized into various treatment groups. Primary tumorgrafts were propagated in vivo. Tumor fragments from donor mice were implanted into small numbers of mice for maintenance, or larger numbers of mice for study initiation. A typical efficacy study design involved administering one or more compounds at various dose levels to tumor-bearing mice.
  • chemotherapeutic agents positive control
  • negative controls were similarly administered and maintained.
  • Routes of administration can include subcutaneous (SC), intraperitoneal (IP), intravenous (IV), intramuscular (IM) and oral (PO). Tumor measurements and body weights were taken over the course of the study and morbidity and mortality were recorded. Necropsy, histopathology, and PCR can also be performed to enhance understanding of disease and drug action.
  • Some of the typical human bladder cancer cell lines, for example transitional cell carcinoma, that were or can be used in the above xenograft models are: HT-1376, HT-1197, UMUC-3, KU-7, and KU-19-19 cell lines.
  • luminal-B type cell lines for example BT-474, or ZR-75
  • basal type cell lines for example, MDA-MB-231, T47D, and Cal-51 cell lines.
  • Some of the typical human lung squamous cell carcinoma cell lines, that were or can be used in the above xenograft models are: SK-MES-1, NCI-H1703, HCC-15, and Calu-1 cell line.
  • Some of the typical human squamous cervical cancer cell lines that were or can be used in the above xenograft models are: A-431 and SiHa cell lines.
  • FaDu and SCC-15 cell lines are typical human squamous head and neck cancer cell lines that were or can be used in the above xenograft models.
  • Some of the typical human lymphoma cell lines that were or can be used in the above xenograft models are: WSU-DLCL2 and OCI-Ly10.
  • CRC human colorectal cancer
  • TT and 8305C Some of the typical human thyroid cancer cell lines that were or can be used in the above xenograft models are: TT and 8305C.
  • CNS central nervous system
  • pancreas cancer cell lines Some of the typical human pancreas cancer cell lines that were or can be used in the above xenograft models are: PANC-1 and BxPC3.
  • SCID mice bearing tumors were randomized and dosed with compounds ranging from, for example, 100 mg/kg to 0.1 mg/kg with different dose scheduling. The mice were dosed for 2-4 weeks. Tumors were measured twice a week using calipers and tumor volumes were calculated using the formula of W 2 ⁇ L/2.
  • Pyrrolopyrimidine Compounds have, or are expected to have, an ED 50 value of ⁇ 100 mg/kg, with some compounds having an ED 50 of ⁇ 10 mg/kg and others an ED 50 of ⁇ 1 mg/kg.

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Abstract

Provided herein are methods for treating or preventing a cancer, in particular solid tumors and hematological cancers, comprising administering to a subject in need thereof an effective amount of a compound of formula (I):
Figure US09623028-20170418-C00001

Description

This application claims the benefit of U.S. Provisional Application No. 62/024,158, filed Jul. 14, 2014, the entire contents of which are incorporated herein by reference.
FIELD
Provided herein are methods for treating or preventing a cancer, in particular solid tumors and hematological cancers as described herein, comprising administering an effective amount of a pyrrolopyrimidine compounds to a subject in need thereof. Also provided herein are Pyrrolopyrimidine Compounds that can be used in said methods.
BACKGROUND
Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia. The neoplastic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host's immune surveillance (Roitt, I., Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993)).
Cancers figure among the leading causes of death worldwide, accounting for 8.2 million deaths in 2012. It is expected that annual cancer cases will rise from 14 million in 2012 to 22 million within the next two decades (See Cancer Fact sheet No 297, World Health Organization, February 2014, retrieved 10 Jun. 2014 and Globocan 2012, IARC).
The current drugs used in cancer treatment are highly toxic and often non-specific. Current anticancer therapy strategies are typically focused on rapid proliferating cells, which can shrink primary and metastatic tumors, but such effects are usually transient and tumor relapse of most metastatic cancers frequently occur. One possible reason for failure is the existence of cancer stem cells. Unlike most cells within the tumor, cancer stem cells are resistant to well-defined chemotherapy, and after treatment, they can regenerate all the cell types in the tumor through their stem cell-like behavior of largely quiescent nature and their abundant expression of drug transporters.
There is an enormous variety of cancers which are described in detail in the medical literature. The incidence of cancer continues to climb as the general population ages, as new cancers develop, and as susceptible populations (e.g., people infected with AIDS or excessively exposed to sunlight) grow. However, options for the treatment of cancer are limited. A tremendous demand therefore exists for new methods and compositions that can be used to treat patients with cancer.
SUMMARY
Provided herein are Pyrrolopyrimidine Compounds that can be used in the methods provided herein.
Provided herein are methods of treating a cancer, in particular a solid tumor or a hematological cancer. The Pyrrolopyrimidine Compound provided herein can be used in the methods for treating or preventing the cancer, in particular the solid tumor or the hematological cancer. The methods comprise administering to a subject in need thereof an effective amount of Pyrrolopyrimidine Compound. Also provided herein are methods for preventing cancer metastasis, comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound as provided herein. The Pyrrolopyrimidine Compound provided herein can be used in the methods for preventing cancer metastasis. Additionally, provided herein are methods of eradicating cancer stem cells in a subject, comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound as provided herein. The Pyrrolopyrimidine Compound provided herein can be used in the methods of eradicating cancer stem cells in a subject. Also provided are methods of inducing differentiation in cancer stem cells in a subject, comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound as provided herein. The Pyrrolopyrimidine Compound provided herein can be used in the methods of inducing differentiation in cancer stem cells in a subject. In another aspect, provided are methods of inducing cancer stem cell death in a subject, comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound as provided herein. The Pyrrolopyrimidine Compound provided herein can be used in the methods of inducing cancer stem cell death in a subject. In yet another aspect, provided herein are methods for treating or preventing a cancer, in particular a solid tumor or hematological cancer, comprising administering to a subject in need thereof an effective amount of a compound that inhibits TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity. The compound that inhibits TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity can be used in the methods for treating or preventing a cancer, in particular a solid tumor or hematological cancer. Also provided are methods for treating or preventing a cancer associated with the pathways involving TTK, CLK1, and CLK2 and mutants or isoforms thereof, comprising administering to a subject in need thereof an effective amount of a compound that inhibits TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity. The compound that inhibits TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity can be used in the methods for treating or preventing a cancer associated with the pathways involving TTK, CLK1, and CLK2 and mutants or isoforms thereof.
The compound that inhibits TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity is a Pyrrolopyrimidine Compound as provided herein.
Compounds useful in the methods disclosed herein are Pyrrolopyrimidine Compounds as described herein, such as, for example, in Table A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or isotopologue thereof.
The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1: Pyrrolopyrimidine Compounds showed anti-proliferative activity in a variety of solid tumors, namely, cancers of the bladder, breast, CNS, colon, endocrine, female GU, head and neck, kidney, liver, lung, pancreas, prostate, skin and soft-tissue (exemplified by Cmpd. 38 in FIG. 1).
FIG. 2: Pyrrolopyrimidine Compounds showed anti-proliferative activity in a variety of hematological cancers, namely, a variety of lymphomas (ST486, CRO-AP2, Faji, MHH-PREB-1, BC-1, DOHH-2, DB, SR, RamosRA1, Daudi, HT, EB-3, SKO-007) and leukemias MOLT-16, BV-173, J-RT3-T3-5, Jurkat, NALM-6, MX1, ARH-77, CML-T1, CCRF-CEM, MV-4-11, EM-2, MOLT-3, CEM-C1, HEL-92-1-7, MEG-01, K-562, THP-1)/myeloma (RPMI-8226, U266B1) (exemplified by Cmpd. 38 in FIG. 2).
FIG. 3: Pyrrolopyrimidine Compounds demonstrated potency against several mesenchymal GBM CSCs (8311, 32612, 81611) with IC50s in the range of 1-2 μM. The data indicated that Pyrrolopyrimidine Compounds, exemplified by Cmpd. 38, are particularly potent against two GBM CSC sphere models derived from proneural subtype GBM patients (52810 and 1912) with IC50 in the range of 50-190 nM.
FIG. 4: Induction of GBM-CSC differentiation by Pyrrolopyrimidine Compounds (for example, Cmpd. 38) is shown in FIG. 4 (left panel: DMSO, right panel: Cmpd. 38). Abbreviations: DMSO=dimethyl sulfoxide; Oct4=octamer-binding transcription factor 4; Tuj1=tubulinβ3; DAPI=4′,6-diamidino-2-phenylindole. The 8311 GBM CSCs and HUAEC cells were allowed to co-culture for 1 day prior to compound administration. After 3 days of compound or mock/DMSO-treatment, cells were fixed and monitored for expression of Oct4 and Tuj1 by indirect immunofluorescence. Pyrrolopyrimidine Compounds (exemplified by Cmpd. 38) induced differentiation of GBM CSCs in the context of a HUAEC co-culture model.
 DETAILED DESCRIPTION Definitions
An “alkyl” group is a saturated, partially saturated, or unsaturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms, typically from 1 to 8 carbons or, in some embodiments, from 1 to 6, 1 to 4, or 2 to 6 or 2 to 4 carbon atoms. Representative alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl and the like. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, —CH═CH(CH3), —CH═C(CH3)2, —C(CH3)═CH2, —C(CH3)═CH(CH3), —C(CH2CH3)═CH2, —C≡CH, —C≡C(CH3), —C≡C(CH2CH3), —CH2C≡CH, —CH2C≡C(CH3) and —CH2C≡C(CH2CH3), among others. An alkyl group can be substituted or unsubstituted. When the alkyl groups described herein are said to be “substituted,” they may be substituted with any substituent or substituents as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or O(alkyl)aminocarbonyl.
A “cycloalkyl” group is a saturated, or partially saturated cyclic alkyl group of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed or bridged rings which can be optionally substituted with from 1 to 3 alkyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl and the like. Examples of unsaturared cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, among others. A cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, by way of example, cyclohexanol and the like.
An “aryl” group is an aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms in the ring portions of the groups. Particular aryls include phenyl, biphenyl, naphthyl and the like. An aryl group can be substituted or unsubstituted. The phrase “aryl groups” also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).
A “heteroaryl” group is an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms. In some embodiments, heteroaryl groups contain 3 to 6 ring atoms, and in others from 6 to 9 or even 6 to 10 atoms in the ring portions of the groups. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.
A “heterocyclyl” is an aromatic (also referred to as heteroaryl) or non-aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S and N. In some embodiments, heterocyclyl groups include 3 to 10 ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. Heterocyclyls can also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring). A heterocycloalkyl group can be substituted or unsubstituted. Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl) groups. The phrase heterocyclyl includes fused ring species, including those comprising fused aromatic and non-aromatic groups, such as, for example, 1- and 2-aminotetraline, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Representative examples of a heterocyclyl group include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), indolinyl, isoindolyl, isoindolinyl, azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, indolizinyl, benzotriazolyl (e.g. 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl (for example, 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one and tetrahydroquinolinyl groups. Representative non-aromatic heterocyclyl groups do not include fused ring species that comprise a fused aromatic group. Examples of non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed below.
A “cycloalkylalkyl” group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl, or both the alkyl and the cycloalkyl portions of the group. Representative cycloalkylalkyl groups include but are not limited to methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, propylcyclopentyl, propylcyclohexyl and the like.
An “aralkyl” group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are defined above. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
An “heterocyclylalkyl” group is a radical of the formula: -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl, or both the alkyl and the heterocyclyl portions of the group. Representative heterocylylalkyl groups include but are not limited to 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyridin-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
A “halogen” is chloro, iodo, bromo, or fluoro.
A “hydroxyalkyl” group is an alkyl group as described above substituted with one or more hydroxy groups.
An “alkoxy” group is —O-(alkyl), wherein alkyl is defined above.
An “alkoxyalkyl” group is -(alkyl)-O-(alkyl), wherein alkyl is defined above.
An “amine” group is a radical of the formula: —NH2.
A “hydroxyl amine” group is a radical of the formula: —N(R#)OH or —NHOH, wherein R# is a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl group as defined herein.
An “alkoxyamine” group is a radical of the formula: —N(R#)O-alkyl or —NHO-alkyl, wherein R# is as defined above.
An “aralkoxyamine” group is a radical of the formula: —N(R#)O-aryl or —NHO-aryl, wherein R# is as defined above.
An “alkylamine” group is a radical of the formula: —NH-alkyl or —N(alkyl)2, wherein each alkyl is independently as defined above.
An “aminocarbonyl” group is a radical of the formula: —C(═O)N(R#)2, —C(═O)NH(R#) or —C(═O)NH2, wherein each R# is as defined above.
An “acylamino” group is a radical of the formula: —NHC(═O)(R#) or —N(alkyl)C(═O)(R#), wherein each alkyl and R# are independently as defined above.
An “O(alkyl)aminocarbonyl” group is a radical of the formula: —O(alkyl)C(═O)N(R#)2, —O(alkyl)C(═O)NH(R#) or —O(alkyl)C(═O)NH2, wherein each R# is independently as defined above.
An “N-oxide” group is a radical of the formula: —N+—O−.
A “carboxy” group is a radical of the formula: —C(═O)OH.
A “ketone” group is a radical of the formula: —C(═O)(R#), wherein R# is as defined above.
An “aldehyde” group is a radical of the formula: —CH(═O).
An “ester” group is a radical of the formula: —C(═O)O(R#) or —OC(═O)(R#), wherein R# is as defined above.
A “urea” group is a radical of the formula: —N(alkyl)C(═O)N(R#)2, —N(alkyl)C(═O)NH(R#), —N(alkyl)C(═O)NH2, —NHC(═O)N(R#)2, —NHC(═O)NH(R#), or —NHC(═O)NH2 #, wherein each alkyl and R# are independently as defined above.
An “imine” group is a radical of the formula: —N═C(R#)2 or —C(R#)═N(R#), wherein each R# is independently as defined above.
An “imide” group is a radical of the formula: —C(═O)N(R#)C(═O)(R#) or —N((C═O)(R#)2, wherein each R# is independently as defined above.
A “urethane” group is a radical of the formula: —OC(═O)N(R#)2, —OC(═O)NH(R#), —N(R#)C(═O)O(R#), or —NHC(═O)O(R#), wherein each R# is independently as defined above.
An “amidine” group is a radical of the formula: —C(═N(R#))N(R#)2, —C(═N(R#))NH(R#), —C(═N(R#))NH2, —C(═NH)N(R#)2, —C(═NH)NH(R#), —C(═NH)NH2, —N═C(R#)N(R#)2, —N═C(R#)NH(R#), —N═C(R#)NH2, —N(R#)C(R#)═N(R#), —NHC(R#)═N(R#), —N(R#)C(R#)═NH, or —NHC(R#)═NH, wherein each R# is independently as defined above.
A “guanidine” group is a radical of the formula: —N(R#)C(═N(R#))N(R#)2, —NHC(═N(R#))N(R#)2, —N(R#)C(═NH)N(R#)2, —N(R#)C(═N(R#))NH(R#), —N(R#)C(═N(R#))NH2, —NHC(═NH)N(R#)2, —NHC(═N(R#))NH(R#), —NHC(═N(R#))NH2, —NHC(═NH)NH(R#), —NHC(═NH)NH2, —N═C(N(R#)2)2, —N═C(NH(R#))2, or —N═C(NH2)2, wherein each R# is independently as defined above.
A “enamine” group is a radical of the formula: —N(R#)C(R#)═C(R#)2, —NHC(R#)═C(R#)2, —C(N(R#)2)═C(R#)2, —C(NH(R#))═C(R#)2, —C(NH2)═C(R#)2, —C(R#)═C(R#)(N(R#)2), —C(R#)═C(R#)(NH(R#)) or —C(R#)═C(R#)(NH2), wherein each R# is independently as defined above.
An “oxime” group is a radical of the formula: —C(═NO(R#))(R#), —C(═NOH)(R#), —CH(═NO(R#)), or —CH(═NOH), wherein each R# is independently as defined above.
A “hydrazide” group is a radical of the formula: —C(═O)N(R#)N(R#)2, —C(═O)NHN(R#)2, —C(═O)N(R#)NH(R#), —C(═O)N(R#)NH2, —C(═O)NHNH(R#)2, or —C(═O)NHNH2, wherein each R# is independently as defined above.
A “hydrazine” group is a radical of the formula: —N(R#)N(R#)2, —NHN(R#)2, —N(R#)NH(R#), —N(R#)NH2, —NHNH(R#)2, or —NHNH2, wherein each R# is independently as defined above.
A “hydrazone” group is a radical of the formula: —C(═N—N(R#)2)(R#)2, —C(═N—NH(R#))(R#)2, —C(═N—NH2)(R#)2, —N(R#)(N═C(R#)2), or —NH(N═C(R#)2), wherein each R# is independently as defined above.
An “azide” group is a radical of the formula: —N3.
An “isocyanate” group is a radical of the formula: —N═C═O.
An “isothiocyanate” group is a radical of the formula: —N═C═S.
A “cyanate” group is a radical of the formula: —OCN.
A “thiocyanate” group is a radical of the formula: —SCN.
A “thioether” group is a radical of the formula; —S(R#), wherein R# is as defined above.
A “thiocarbonyl” group is a radical of the formula: —C(═S)(R#), wherein R# is as defined above.
A “sulfinyl” group is a radical of the formula: —S(═O)(R#), wherein R# is as defined above.
A “sulfone” group is a radical of the formula: —S(═O)2(R#), wherein R# is as defined above.
A “sulfonylamino” group is a radical of the formula: —NHSO2(R#) or —N(alkyl)SO2(R#), wherein each alkyl and R# are defined above.
A “sulfonamide” group is a radical of the formula: —S(═O)2N(R#)2, or —S(═O)2NH(R#), or —S(═O)2NH2, wherein each R# is independently as defined above.
A “phosphonate” group is a radical of the formula: —P(═O)(O(R#))2, —P(═O)(OH)2, —OP(═O)(O(R#))(R#), or —OP(═O)(OH)(R#), wherein each R# is independently as defined above.
A “phosphine” group is a radical of the formula: —P(R#)2, wherein each R# is independently as defined above.
When the groups described herein, with the exception of alkyl group, are said to be “substituted,” they may be substituted with any appropriate substituent or substituents. Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amine; alkylamine; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (═O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.
As used herein, the term “Pyrrolopyrimidine Compound” refers to compounds of formula (I), as well as to further embodiments provided herein. In one embodiment, a “Pyrrolopyrimidine Compound” is a compound set forth in Table 1. The term “Pyrrolopyrimidine Compound” includes pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers and isotopologues of the compounds provided herein.
As used herein, the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts of the compounds of formula (I) include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, maleic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate salts. Others are well-known in the art, see for example, Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton Pa. (1990) or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton Pa. (1995).
As used herein and unless otherwise indicated, the term “stereoisomer” or “stereomerically pure” means one stereoisomer of a Pyrrolopyrimidine Compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. The Pyrrolopyrimidine Compounds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.
The use of stereomerically pure forms of such Pyrrolopyrimidine Compounds, as well as the use of mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular Pyrrolopyrimidine Compound may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).
It should also be noted the Pyrrolopyrimidine Compounds can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof. In certain embodiments, the Pyrrolopyrimidine Compounds are isolated as either the E or Z isomer. In other embodiments, the Pyrrolopyrimidine Compounds are a mixture of the E and Z isomers.
“Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
Figure US09623028-20170418-C00002
As readily understood by one skilled in the art, a wide variety of functional groups and other stuctures may exhibit tautomerism and all tautomers of compounds of formula (I) are within the scope of the present invention.
It should also be noted the Pyrrolopyrimidine Compounds can contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) sulfur-35 (35S), or carbon-14 (14C), or may be isotopically enriched, such as with deuterium (2H), carbon-13 (13C), or nitrogen-15 (15N). As used herein, an “isotopologue” is an isotopically enriched compound. The term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term “isotopic composition” refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically encriched compounds are useful as therapeutic agents, e.g., breast cancer therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the Pyrrolopyrimidine Compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, there are provided isotopologues of the Pyrrolopyrimidine Compounds, for example, the isotopologues are deuterium, carbon-13, or nitrogen-15 enriched Pyrrolopyrimidine Compounds.
It should be noted that if there is a discrepancy between a depicted structure and a name for that structure, the depicted structure is to be accorded more weight.
“Treating” as used herein, means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. In one embodiment, the disorder is a cancer, in particular, a solid tumor or hematological cancer. In some embodiments, “treating” means an alleviation, in whole or in part, of a cancer, or symptoms associated with a cancer, in particular, a solid tumor or hematological cancer, or a slowing, or halting of further progression or worsening of those symptoms.
“Preventing” as used herein, means a method of delaying and/or precluding the onset, recurrence or spread, in whole or in part, of a cancer, in particular, a solid tumor or hematological cancer; barring a subject from acquiring a cancer, in particular, a solid tumor or hematological cancer; or reducing a subject's risk of acquiring a cancer, in particular, a solid tumor or hematological cancer.
The term “effective amount” in connection with a Pyrrolopyrimidine Compound means an amount capable of treating or preventing cancer, in particular, a solid tumor or hematological cancer, or symptoms thereof, as disclosed herein. The effective amount of Pyrrolopyrimidine Compound, for example in a pharmaceutical composition, may be at a level that will exercise the desired effect; for example, about 0.005 mg/kg of a subject's body weight to about 100 mg/kg of a patient's body weight in unit dosage for parenteral administration. As will be apparent to those skilled in the art, it is to be expected that the effective amount of a Pyrrolopyrimidine Compound disclosed herein may vary depending on the severity of the indication being treated.
The terms “patient” and “subject” as used herein include an animal, including, but not limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human. In one embodiment, a subject is a human having or at risk for having cancer, in particular, a solid tumor or hematological cancer, or symptoms thereof. In one embodiment, a patient is a human having histologically or cytologically-confirmed solid tumor or hematological cancer, including subjects who have progressed on (or not been able to tolerate) standard anticancer therapy or for whom no standard anticancer therapy exists.
As used herein, and unless otherwise specified, the terms “cancer” refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include solid tumors and hematological cancer. In some embodiments, the cancer is a primary cancer, in others, the cancer is metastasized.
As used herein “solid tumors” includes, but is not limited to, bladder cancer (including, but not limited to, superficial bladder cancer), breast cancer (including, but not limited to, luminal B type, ER+, PR+ and Her2+ breast cancer), central nervous system cancer (including, but no tlimited to, glioblastoma multiforme (GBM), glioma, medulloblastoma, and astrocytoma), colorectal cancer, gastrointestinal cancer (including, but not limited to, stomach cancer, oesophagus cancer, and rectum cancer), endocrine cancer (including, but not imited to, thyroid cancer, and adrenal gland cancer), eye cancer (including, but not limited to, retinoblastoma), female genitourinary cancer (including, but not limited to, cancer of the placenta, uterus, vulva, ovary, cervix), head and neck cancer (including, but not limited to, cancer of the pharynx, oesophagus, and tongue), liver cancer, lung cancer (including, but not limited to, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), mucoepidermoid, bronchogenic, squamous cell carcinoma (SQCC), and analplastic/NSCLC), skin cancer (including, but not limited to, melanoma, and SQCC), soft tissue cancer (including but not limited to, sarcoma, Ewing's sarcoma, and rhabdomyosarcoma), bone cancer (including, but not limited to, sarcoma, Ewing's sarcoma, and osteosarcoma), squamous cell cancer (including, but not limited to, lung, esophageal, cervical, and head and neck cancer), pancreas cancer, kidney cancer (including, but not limited to, renal Wilm's tumor and renal cell carcinoma), and prostate cancer. In one embodiment, the solid tumor is not triple negative breast cancer (TNBC). In some embodiments, the solid tumor is breast cancer, colon cancer, lung cancer or bladder cancer. In one such embodiment, the solid tumor is superficial bladder cancer. In another, the solid tumor is lung squamous cell carcinoma. In yet another embodiment, the solid tumor is luminal B type breast cancer.
As used herein “hematological cancer” includes, but is not limited to, leukemia (including, but not limited to, acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), acute T-cell leukemia, B cell precursor leukemia, acute promyelocytic leukemia (APML), plasma cell leukemia, myelomonoblastic/T-ALL, B myelomonocytic leukemia, erythroleukemia, and acute myeloid leukemia (AML)), lymphoma (including but not limited to Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), B cell lymphoma, lymphoblastic lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), large cell immunoblastic lymphoma), and multiple myeloma.
In the context of a cancer, inhibition may be assessed by inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor-related symptoms, inhibition of tumor secreted factors (including tumor secreted hormones, such as those that contribute to carcinoid syndrome), delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), increased Overall Survival (OS), among others. OS as used herein means the time from randomization until death from any cause, and is measured in the intent-to-treat population. TTP as used herein means the time from randomization until objective tumor progression; TTP does not include deaths. As used herein, PFS means the time from randomization until objective tumor progression or death. In one embodiment, PFS rates will be computed using the Kaplan-Meier estimates. In the extreme, complete inhibition, is referred to herein as prevention or chemoprevention. In this context, the term “prevention” includes either preventing the onset of clinically evident cancer altogether or preventing the onset of a preclinically evident stage of a cancer. Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing a cancer.
In certain embodiments, the treatment of lymphoma may be assessed by the International Workshop Criteria (IWC) for non-Hodgkin lymphoma (NHL) (see Cheson B D, Pfistner B, Juweid, M E, et. al. Revised Response Criteria for Malignant Lymphoma. J. Clin. Oncol: 2007: (25) 579-586), using the response and endpoint definitions shown below:
Response Definition Nodal Masses Spleen, liver Bone Marrow
CR Disappearance (a) FDG-avid or Not palpable, Infiltrate cleared on
of all evidence PET positive prior nodules repeat biopsy; if
of disease to therapy; mass disappeared indeterminate by
of any size morphology,
permitted if PET immunohistochemistry
negative should be negative
(b) Variably FDG-
avid or PET
negative;
regression to
normal size on CT
PR Regression of ≧50% decrease in ≧50% decrease Irrelevant if positive
measurable SPD of up to 6 in SPD of nodules prior to therapy; cell
disease and largest dominant (for single nodule type should be
no new sites masses; no in greatest specified
increase in size of transverse
other nodes diameter); no
(a) FDG-avid or increase in size
PET positive prior of liver or spleen
to therapy; one or
more PET positive
at previously
involved site
(b) Variably FDG-
avid or PET
negative;
regression on CT
SD Failure to attain (a) FDG-avid or
CR/PR or PD PET positive prior
to therapy; PET
positive at prior
sites of disease
and no new sites
on CT or PET
(b) Variably FDG-
avid or PET
negative; no
change in size of
previous lesions
on CT
PD or Any new lesion Appearance of a ≧50% increase New or recurrent
relapsed or increase by new lesion(s) ≧1.5 from nadir in the involvement
disease ≧50% of cm in any axis, SPD of any
previously ≧50% increase in previous lesions
involved sites SPD of more than
from nadir one node,
or ≧50% increase
in longest
diameter of a
previously
identifed node
≧1 cm in short
axis
Lesions PET
positive if FDG-
avid lymphoma or
PET positive prior
to therapy
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable disease; PD, progressive disease.
End point Patients Definition Measured from
Primary
Overall survival All Death as a result of any Entry onto
cause study
Progression-free All Disease progression or death Entry onto
survival as a result of any cause study
Secondary
Event-free All Failure of treatment or death Entry onto
survival as result of any cause study
Time to All Time to progression or death Entry onto
progression as a result of lymphoma study
Disease-free In CR Time to relapse or death as a Documentation
survival result of lymphoma or acute of response
toxicity of treatment
Response In CR Time to relapse or Documentation
duration or PR progression of response
Lymphoma- All Time to death as a result of Entry onto
specific survival lymphoma study
Time to next All Time to new treatment End of primary
treatment treatment

Abbreviations: CR: complete remission; PR: partial remission.
In one embodiment, the end point for lymphoma is evidence of clinical benefit. Clinical benefit may reflect improvement in quality of life, or reduction in patient symptoms, transfusion requirements, frequent infections, or other parameters. Time to reappearance or progression of lymphoma-related symptoms can also be used in this end point.
In certain embodiments, the treatment of CLL may be assessed by the International Workshop Guidelines for CLL (see Hallek M, Cheson B D, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood, 2008; (111) 12: 5446-5456) using the response and endpoint definitions shown therein and in particular:
Parameter CR PR PD
Group A
Lymphadenopathy† None >1.5 cm Decrease ≧50% Increase ≧50%
Hepatomegaly None Decrease ≧50% Increase ≧50%
Splenomegaly None Decrease ≧50% Increase ≧50%
Blood lymphocytes <4000/μL Decrease ≧50% Increase ≧50%
from baseline over baseline
Marrow‡ Normocellular, 50% reduction
<30% in marrow
lymphocytes, infiltrate, or
no B-lymphoid B-lymphoid
nodules. nodules
Hypocellular
marrow defines
CRi (5.1.6).
Group B
Platelet count >100 000/μL >100 000/μL Decrease of
or increase ≧50% ≧50% from
over baseline baseline
secondary to
CLL
Hemoglobin >11.0 g/dL >11 g/dL or Decrease of
increase ≧50% >2 g/dL from
over baseline baseline
secondary to
CLL
Neutrophils‡ >1500/μL >1500/μL or
>50%
improvement
over baseline
Group A criteria define the tumor load; Group B criteria define the function of the hematopoietic system (or marrow). CR (complete remission): all of the criteria have to be met, and patients have to lack disease-related constitutional symptoms; PR (partial remission): at least two of the criteria of group A plus one of the criteria of group B have to be met; SD is absence of progressive disease (PD) and failure to achieve at least a PR; PD: at least one of the above criteria of group A or group B has to be met. Sum of the products of multiple lymph nodes (as evaluated by CT scans in clinical trials, or by physical examination in general practice). These parameters are irrelevant for some response categories.
In certain embodiments, the treatment of multiple myeloma may be assessed by the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie B G M, Harousseau J-L, Miguel J S, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006; (10) 10: 1-7), using the response and endpoint definitions shown below:
Response
Subcategory Response Criteriaa
sCR CR as defined below plus
Normal FLC ratio and
Absence of clonal cells in bone marrowb by
immunohistochemistry or immunofluorescencec
CR Negative immunofixation on the serum and urine and
Disappearance of any soft tissue plasmacytomas and
<5% plasma cells in bone marrowb
VGPR Serum and urine M-protein detectable by
immunofixation but not on electrophoresis or 90% or
greater reduction in serum M-protein plus urine
M-protein level <100mg per 24 h
PR ≧50% reduction of serum M-protein and reduction in
24-h urinary M-protein by ≧90% or to <200 mg per 24 h
If the serum and urine M-protein are unmeasurable,d a
≧50% decrease in the difference between involved and
uninvolved FLC levels is required in place of the
M-protein criteria
If serum and urine M-protein are unmeasurable, and
serum free light assay is also unmeasurable, ≧50%
reduction in plasma cells is required in place of
M-protein, provided baseline bone marrow plasma cell
percentage was ≧30%
In addition to the above listed criteria, if present at
baseline, a ≧50% reduction in the size of soft tissue
plasmacytomas is also required
SD (not Not meeting criteria for CR, VGPR, PR or progressive
recommended disease
for use as an
indicator of
response;
stability of
disease is best
described by
providing the
time to
progression
estimates)
Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease; sCR, stringent complete response; VGPR, very good partial response; aAll response categories require two consecutive assessments made at anytime before the institution of any new therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements; bConfirmation with repeat bone marrow biopsy not needed; cPresence/absence of clonal cells is based upon the κ/λ ratio. An abnormal κ/λ ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is κ/λ of >4:1 or <1:2. dMeasurable disease defined by at least one of the following measurements: Bone marrow plasma cells ≧30%; Serum M-protein ≧1 g/dl (≧10 gm/l)[10 g/l]; Urine M-protein ≧200 mg/24 h; Serum FLC assay: Involved FLC level ≧10 mg/dl (≧100 mg/l); provided serum FLC ratio is abnormal.
In certain embodiments, the treatment of a cancer may be assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (see Thereasse P., et al. New Guidelines to Evaluate the Response to Treatment in Solid Tumors. J. of the National Cancer Institute; 2000; (92) 205-216 and Eisenhauer E. A., Therasse P., Bogaerts J., et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European J. Cancer; 2009; (45) 228-247). Overall responses for all possible combinations of tumor responses in target and non-target lesions with our without the appearance of new lesions are as follows:
Non-target Overall
Target lesions lesions New lesions response
CR CR No CR
CR Incomplete No PR
response/SD
PR Non-PD No PR
SD Non-PD No SD
PD Any Yes or no PD
Any PD Yes or no PD
Any Any Yes PD
CR = complete response;
PR = partial response;
SD = stable disease; and
PD = progressive disease.
With respect to the evaluation of target lesions, complete response (CR) is the disappearance of all target lesions, partial response (PR) is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, progressive disease (PD) is at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions and stable disease (SD) is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started.
With respect to the evaluation of non-target lesions, complete response (CR) is the disappearance of all non-target lesions and normalization of tumor marker level; incomplete response/stable disease (SD) is the persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits, and progressive disease (PD) is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
The procedures, conventions, and definitions described below provide guidance for implementing the recommendations from the Response Assessment for Neuro-Oncology (RANO) Working Group regarding response criteria for high-grade gliomas (Wen P., Macdonald, D R., Reardon, D A., et al. Updated response assessment criteria for highgrade gliomas: Response assessment in neuro-oncology working group. J Clin Oncol 2010; 28: 1963-1972). Primary modifications to the RANO criteria for Criteria for Time Point Responses (TPR) can include the addition of operational conventions for defining changes in glucocorticoid dose, and the removal of subjects' clinical deterioration component to focus on objective radiologic assessments. The baseline MRI scan is defined as the assessment performed at the end of the post-surgery rest period, prior to re-initiating compound treatment. The baseline MRI is used as the reference for assessing complete response (CR) and partial response (PR). Whereas, the smallest SPD (sum of the products of perpendicular diameters) obtained either at baseline or at subsequent assessments will be designated the nadir assessment and utilized as the reference for determining progression. For the 5 days preceding any protocol-defined MRI scan, subjects receive either no glucocorticoids or are on a stable dose of glucocorticoids. A stable dose is defined as the same daily dose for the 5 consecutive days preceding the MRI scan. If the prescribed glucocorticoid dose is changed in the 5 days before the baseline scan, a new baseline scan is required with glucocorticoid use meeting the criteria described above. The following definitions will be used.
Measurable Lesions: Measurable lesions are contrast-enhancing lesions that can be measured bidimensionally. A measurement is made of the maximal enhancing tumor diameter (also known as the longest diameter, LD). The greatest perpendicular diameter is measured on the same image. The cross hairs of bidimensional measurements should cross and the product of these diameters will be calculated.
Minimal Diameter: T1-weighted image in which the sections are 5 mm with 1 mm skip. The minimal LD of a measurable lesion is set as 5 mm by 5 mm. Larger diameters may be required for inclusion and/or designation as target lesions. After baseline, target lesions that become smaller than the minimum requirement for measurement or become no longer amenable to bidimensional measurement will be recorded at the default value of 5 mm for each diameter below 5 mm. Lesions that disappear will be recorded as 0 mm by 0 mm.
Multicentric Lesions: Lesions that are considered multicentric (as opposed to continuous) are lesions where there is normal intervening brain tissue between the two (or more) lesions. For multicentric lesions that are discrete foci of enhancement, the approach is to separately measure each enhancing lesion that meets the inclusion criteria. If there is no normal brain tissue between two (or more) lesions, they will be considered the same lesion.
Nonmeasurable Lesions: All lesions that do not meet the criteria for measurable disease as defined above will be considered non-measurable lesions, as well as all nonenhancing and other truly nonmeasurable lesions. Nonmeasurable lesions include foci of enhancement that are less than the specified smallest diameter (i.e., less than 5 mm by 5 mm), nonenhancing lesions (e.g., as seen on T1-weighted post-contrast, T2-weighted, or fluid-attenuated inversion recovery (FLAIR) images), hemorrhagic or predominantly cystic or necrotic lesions, and leptomeningeal tumor. Hemorrhagic lesions often have intrinsic T1-weighted hyperintensity that could be misinterpreted as enhancing tumor, and for this reason, the pre-contrast T1-weighted image may be examined to exclude baseline or interval sub-acute hemorrhage.
At baseline, lesions will be classified as follows: Target lesions: Up to 5 measurable lesions can be selected as target lesions with each measuring at least 10 mm by 5 mm, representative of the subject's disease; Non-target lesions: All other lesions, including all nonmeasurable lesions (including mass effects and T2/FLAIR findings) and any measurable lesion not selected as a target lesion. At baseline, target lesions are to be measured as described in the definition for measurable lesions and the SPD of all target lesions is to be determined. The presence of all other lesions is to be documented. At all post-treatment evaluations, the baseline classification of lesions as target and non-target lesions will be maintained and lesions will be documented and described in a consistent fashion over time (e.g., recorded in the same order on source documents and eCRFs). All measurable and nonmeasurable lesions must be assessed using the same technique as at baseline (e.g., subjects should be imaged on the same MRI scanner or at least with the same magnet strength) for the duration of the study to reduce difficulties in interpreting changes. At each evaluation, target lesions will be measured and the SPD calculated. Non-target lesions will be assessed qualitatively and new lesions, if any, will be documented separately. At each evaluation, a time point response will be determined for target lesions, non-target lesions, and new lesion. Tumor progression can be established even if only a subset of lesions is assessed. However, unless progression is observed, objective status (stable disease, PR or CR) can only be determined when all lesions are assessed.
Confirmation assessments for overall time point responses of CR and PR will be performed at the next scheduled assessment, but confirmation may not occur if scans have an interval of <28 days. Best response, incorporating confirmation requirements, will be derived from the series of time points.
TTK (also known as Mps1, hMps1 or PYT) is a dual specificity protein kinase with the ability to phosphorylate tyrosine, serine and threonine. Associated with cell proliferation, this protein is essential for chromosome alignment at the centromere during mitosis and is required for centrosome duplication. It has been found to be a critical mitotic checkpoint protein for accurate segregation of chromosomes during mitosis. Tumorigenesis may occur when this protein fails to degrade and produces excess centrosomes resulting in aberrant mitotic spindles. Alternative splicing results in multiple transcript variants. [RefSeq, November 2009]. TTK is essential for spindle checkpoint function and its inhibition accelerates cell progression through mitosis. TTK also plays an important role for cancer stem cell survival.
CLK1 is a member of the CDC2-like (or LAMMER) family of dual specificity protein kinases. In the nucleus, the encoded protein phosphorylates serine/arginine-rich (SR) proteins involved in pre-mRNA processing, releasing them into the nucleoplasm. The choice of splice sites during pre-mRNA processing may be regulated by the concentration and localization of splicing factors, including serine/arginine rich (SR) proteins. Therefore, the encoded protein may play an indirect role in governing splice site selection. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, June 2009]
CLK2 is a member of the CLK family of dual specificity protein kinases. CLK family members have been shown to interact with, and phosphorylate, serine/arginine-rich (SR) proteins of the spliceosomal complex, which is a part of the regulatory mechanism that enables the SR proteins to control RNA splicing. This protein kinase is involved in the regulation of several cellular processes and may serve as a link between cell cycle progression, apoptosis, and telomere length regulation [RefSeq, July 2008]. Inhibition of CLK2 changes the expression of protein isoforms, many of which contribute to the oncogenic phenotype.
CAMKK2 belongs to the serine/threonine-specific protein kinase family, and to the Ca++/calmodulin-dependent protein kinase subfamily. This protein plays a role in the calcium/calmodulin-dependent (CaM) kinase cascade by phosphorylating the downstream kinases CaMK1 and CaMK4 [RefSeq, July 2012]. CAMKK2 reportedly plays a role in tumor energy homeostasis.
Pyrrolopyrimidine Compounds
Provided herein are compounds having the following formula (I):
Figure US09623028-20170418-C00003
and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and isotopologues thereof,
wherein:
R1 is substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclyl;
R2 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl, and
L is NH or O;
provided that when L is NH, R3 is not pyridyl.
Provided herein are compounds having the following formula (I):
Figure US09623028-20170418-C00004
and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and isotopologues thereof,
wherein:
R1 is substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclyl;
R2 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl, and
L is NH or O;
provided
R3 is not pyridyl when L is NH or when R2 is pyrazolyl; and
the compound is not
  • N-methyl-N-[trans-3-[[5-(1-methyl-1H-pyrazol-4-yl)-2-[(1-methyl-1Hpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]cyclobutyl]-2-propenamide; or
  • N-methyl-N-[trans-3-[[5-(1-methyl-1H-pyrazol-3-yl)-2-[(1-methyl-1Hpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]cyclobutyl]-2-propenamide.
The compound as described herein is not a compound selected from:
Figure US09623028-20170418-C00005
Figure US09623028-20170418-C00006
As described herein, the compound is not
Figure US09623028-20170418-C00007
Figure US09623028-20170418-C00008
In one embodiment, the compound is not N-methyl-N-[trans-3-[[5-(1-methyl-1H-pyrazol-4-yl)-2-[(1-methyl-1Hpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]cyclobutyl]-2-propenamide (also named N-methyl-N-((1r,3r)-3-((5-(1-methyl-1H-pyrazol-4-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)cyclobutyl)acrylamide)
Figure US09623028-20170418-C00009
or N-methyl-N-[trans-3-[[5-(1-methyl-1H-pyrazol-3-yl)-2-[(1-methyl-1Hpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]cyclobutyl]-2-propenamide (also named N-methyl-N-((1r,3r)-3-((5-(1-methyl-1H-pyrazol-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)cyclobutyl)acrylamide)
Figure US09623028-20170418-C00010
In yet another embodiment, the compound is not
Figure US09623028-20170418-C00011
In one embodiment, provided herein are compounds of formula (I), wherein L is O.
In some embodiments of compounds of formula (I), R1 is substituted or unsubstituted alkyl, for example, R1 is substituted or unsubstituted methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl, or 2,2-dimethylpropyl. In some embodiments, R1 is substituted or unsubstituted methyl, ethyl, isopropyl, sec-butyl, t-butyl, or 2,2-dimethylpropyl. In some embodiments of formula (I), wherein R1 is alkyl, the alkyl is substituted with one or more —OR or —NR2, wherein each R is independently —H or substituted or unsubstituted (C1-4)alkyl. For example R1 is —CH2CH2OH, —CH2CH2OCH3, or —CH2CH2NHCH3. In other embodiments of compounds of formula (I), R1 is substituted or unsubstituted C3-8 cycloalkyl, for example, R1 is substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some such embodiments, the cycloalkyl is substituted with one or more —CN, halogen, —OR or a substituted or unsubstituted C1-3 alkyl, wherein each R is independently —H or substituted or unsubstituted (C1-4)alkyl. For example, in some embodiments the cycloalkyl is substituted with one or more —CN, —F, —OH, or —CH3. In some other embodiments of compounds of formula (I), R1 is substituted or unsubstituted non-aromatic heterocyclyl, for example, R1 is substituted or unsubstituted oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or piperidinyl.
In some other embodiments of compounds of formula (I), R1 is substituted or unsubstituted C1-8 alkyl,
Figure US09623028-20170418-C00012
wherein
each R′ is independently —CN, halogen, —OR or C1-3 alkyl;
R″ is —H or C1-3 alkyl;
    • each R is independently —H or substituted or unsubstituted (C1-4)alkyl; and
n is 0-2.
In some such embodiments, R1 is substituted or unsubstituted methyl, ethyl, isopropyl, sec-butyl, t-butyl, or 2,2-dimethylpropyl,
Figure US09623028-20170418-C00013
and R′ is —CN, —F, —OH, or —CH3;
R″ is —CH3;
n is 0, 1 or 2; and
q is 0 or 1.
Also provided herein are compounds of formula (I), wherein R2 is substituted phenyl. In some such embodiments, R2 is phenyl, substituted with one or more substituted or unsubstituted C1-6 alkyl, halogen, —CN, —OR5, —C(═O)NR5 2, —C(═O) (substituted or unsubstituted heterocyclyl), —C(═O) (substituted or unsubstituted alkylheterocyclyl), —NHC(═O)R5, —SO2NR5 2, or substituted or unsubstituted heteroaryl, wherein each R5 is independently —H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkylheterocyclyl. For example, R2 is phenyl, substituted with one or more —(C1-3 alkyl), —(C1-3 alkyl)NR2, —CF3, —Cl, —F, —CN, —OCH3, —OCF3, —C(═O)NR2, —C(═O)NR (substituted or unsubstituted cycloalkyl), —C(═O)NR(CH2)0-2CR2(CH2)0-2OR, —C(═O)NR(CH2)0-2CR2(CH2)0-2NR2, —C(═O)NR(CH2)0-2CR2(CH2)0-2C(═O)NR2, —C(═O)N (substituted or unsubstituted cycloalkyl)(CH2)0-2OR, —C(═O)NR(CH2)0-3 (substituted or unsubstituted heterocyclyl), —C(═O)(CH2)0-3 (substituted or unsubstituted heterocyclyl), —C(═NR)NR2, —NRC(═O)R, —SO2NR2, —SO2R, or substituted or unsubstituted heterocyclyl, wherein each R is independently —H or substituted or unsubstituted (C1-4)alkyl. In some such embodiments, each R is independently —H or —CH3.
In some embodiments of compounds of formula (I), R2 is phenyl, substituted with one or more —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —CH2NH2, —CF3, —Cl, —F, —CN, —OCH3, —OCF3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, —C(═O)NC(CH3)3, —C(═O)NHCH2CH2F, —C(═O)NHCH2CHF2, —C(═O)NHCH2CF3, —C(═O)NHCH2CF2CH3, —C(═O)NHCH2CN, —C(═O)N(CH3)CH2CN, —C(═O)NHCH2CH2CN, —C(═O)N(CH3)CH2CH2CN, —C(═O)NH-cyclobutyl, —C(═O)NH-(hydroxy-cyclobutyl), —C(═O)NH-cyclopentyl, —C(═O)NH-(hydroxyl-cyclopentyl), —C(═O)NHCH2CH2OH, —C(═O)NHCH2CH2OCH3, —C(═O)N(CH3)CH2CH2OH, —C(═O)N(CH3)CH2CH2OCH3, —C(═O)NHCH2CH2CH2OH, —C(═O)N(CH3)CH2CH2CH2OH, —C(═O)N(CH3)CH2CH2CH2OCH3, —C(═O)NHCH2CH(CH3)OH, —C(═O)NHCH2C(CH3)2OH, —C(═O)NHCH(CH3)CH2OH, —C(═O)NHC(CH3)2CH2OH, —C(═O)NHCH2CH2NH2, —C(═O)NHCH2CH2NH(CH3), —C(═O)NHCH2CH2N(CH3)2, —C(═O)NHCH2C(═O)NH2, —C(═O)N(CH3)CH2C(═O)NH2, —C(═O)NHCH2CH2C(═O)NH2, —C(═O)N(CH3)CH2CH2C(═O)NH2, —C(═O)N(cyclopropyl)CH2CH2OH, —C(═O)NH-oxetanyl, —C(═O)N(CH3)-oxetanyl, —C(═O)NH-(methyl-oxetanyl), —C(═O)NH-azetidinyl, —C(═O)NH-(methylazetidinyl), —C(═O)NH-(1-acetylazetidinyl), —C(═O)NH-pyrrolidyl, —C(═O)NH-piperidyl, —C(═O)NH-tetrahydrofuranyl, —C(═O)N(CH3)-tetrahydrofuranyl, —C(═O)NH-tetrahydropyranyl, —C(═O)N(CH3)-tetrahydropyranyl, —C(═O)NHCH2-oxetanyl, —C(═O)N(CH3)CH2-oxetanyl, —C(═O)NHCH2-(methyl-oxetanyl), —C(═O)N(CH3)CH2-(methyl-oxetanyl), —C(═O)NHCH2-tetrahydrofuranyl, —C(═O)NHCH2-tetrahydropyranyl, —C(═O)NHCH2-dioxanyl, —C(═O)aziridinyl, —C(═O)(methyl-aziridinyl), —C(═O)(dimethyl-aziridinyl), —C(═O)(hydroxymethyl-aziridinyl), —C(═O)azetidinyl, —C(═O)pyrrolidinyl, —C(═O)(hydroxyl-pyrrolidinyl), —C(═O)(hydroxyl, methoxypyrrolidinyl), —C(═O)(dimethoxypyrrolidinyl), —C(═O)morpholinyl, —C(═O)piperazinyl, —C(═O)(methylpiperazinyl), —C(═O)(hydroxy-piperidyl), —C(═O)(fluoropiperidinyl), —(C═O)(methoxy-piperidyl), —C(═NH)NH2, —NHC(═O)CH3, —SO2NHCH3, —SO2CH3, or substituted or unsubstituted pyrazolyl. In some other embodiments, R2 is phenyl, substituted with one or more —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —CH2NH2, —CF3, —Cl, —F, —CN, —OCH3, —OCF3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, —C(═O)NC(CH3)3, —C(═O)NHCH2CH2F, —C(═O)NHCH2CF2CH3, —C(═O)N(CH3)CH2CN, —C(═O)N(CH3)CH2CH2CN, —C(═O)NH-(3-hydroxy-cyclobutyl), —C(═O)NH-cyclopentyl, —C(═O)NH-(2-hydroxycyclopentyl), —C(═O)NHCH2CH2OH, —C(═O)NHCH2CH2OCH3, —C(═O)N(CH3)CH2CH2OH, —C(═O)N(CH3)CH2CH2OCH3, —C(═O)NHCH2CH2CH2OH, —C(═O)N(CH3)CH2CH2CH2OH, —C(═O)NHCH2CH(CH3)OH, —C(═O)NHCH2C(CH3)2OH, —C(═O)NHCH(CH3)CH2OH, —C(═O)NHC(CH3)2CH2OH, —C(═O)NHCH2CH2NH2, —C(═O)NHCH2CH2NH(CH3), —C(═O)NHCH2CH2N(CH3)2, —C(═O)N(CH3)CH2C(═O)NH2, —C(═O)N(CH3)CH2CH2C(═O)NH2, —C(═O)N(cyclopropyl)CH2CH2OH, —C(═O)NH-oxetanyl, —C(═O)N(CH3)-oxetanyl, —C(═O)NH-(3-methyl-oxetanyl), —C(═O)NH-(1-methylazetidinyl), —C(═O)NH-(1-acetylazetidinyl), —C(═O)NH-piperidyl, —C(═O)NH-tetrahydrofuranyl, —C(═O)NH-tetrahydropyranyl, —C(═O)N(CH3)-tetrahydropyranyl, —C(═O)NHCH2-oxetanyl, —C(═O)N(CH3)CH2-(3-methyl-oxetanyl), —C(═O)NHCH2-tetrahydrofuranyl, —C(═O)NHCH2-tetrahydropyranyl, —C(═O)NHCH2-dioxanyl, —C(═O)aziridinyl, —C(═O)(2-methyl-aziridinyl), —C(═O)(2,2-dimethyl-aziridinyl), —C(═O)(2-(hydroxymethyl)aziridinyl), —C(═O)azetidinyl, —C(═O)pyrrolidinyl, —C(═O)(3-hydroxy-4-methoxypyrrolidinyl), —C(═O)(3,4-dimethoxypyrrolidinyl), —C(═O)morpholinyl, —C(═O)piperazinyl, —C(═O)(4-methylpiperazinyl), —C(═O)(4-hydroxy-piperidyl), —C(═O)(4,4-difluoropiperidinyl), —(C═O)(4-methoxy-piperidyl), —C(═NH)NH2, —NHC(═O)CH3, —SO2NHCH3, —SO2CH3, or substituted or unsubstituted pyrazolyl.
In some embodiments of compounds of formula (I), R2 is substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted indazolyl or substituted or unsubstituted isoindolinone. In some such embodiments, R2 is substituted with one or more halogen, substituted or unsubstituted (C1-4)alkyl, —OR, —C(═O)NR2, or substituted or unsubstituted heterocyclyl, wherein each R is independently —H or substituted or unsubstituted (C1-4)alkyl. For example, R2 is pyrazolyl substituted with one or more —Cl, —CH3, —CH2CH3, —CH(CH3)2, —CH2CH2OCH3, —CH2C(CH3)2OH, or tetrahydropyranyl. Alternatively, R2 is pyridyl, substituted with one or more —OCH3, C(═O)NHCH3, or tetrahydropyranyl. In yet other embodiments, R2 is indazolyl or isoindolinone, substituted with one or more —CH3.
In some such embodiments of R2, R1 is substituted or unsubstituted C1-8 alkyl,
Figure US09623028-20170418-C00014
wherein
each R′ is independently —OR or C1-3 alkyl;
R″ is —H or C1-3 alkyl;
each R is independently —H or substituted or unsubstituted (C1-4)alkyl; and
n is 0-2.
In yet other embodiments of compounds of formula (I), R3 is substituted or unsubstituted heterocyclyl, for example, substituted or unsubstituted pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, benztriazolyl, indazolyl, indolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzoxazolonyl, benzoxadiazolyl, benzimidazolyl, or quinolyl. In some such embodiments, the heterocyclyl is substituted with one or more substituents selected from substituted or unsubstituted (C1-4)alkyl, halogen, —OR, —CN, —NR2, —C(═O)NR2, —NRC(═O)R, or substituted or unsubstituted triazolyl, wherein each R is independently —H or substituted or unsubstituted (C1-4)alkyl. For example, the heterocyclyl is substituted with one or more substituents selected from —CH3, —CH(CH3)2, —F, —Cl, —OH, —OCH3, —OCH2CH3, —CN, —NH2, —NHCH3, —N(CH3)2, —C(═O)NH(CH3), —NHC(═O)CH3, or substituted or unsubstituted triazolyl. In some such embodiments, the pyrazolyl is substituted with one or more —CH3, or —Cl. In others, the pyridyl is substituted with one or more —CH3, —F, —Cl, —OH, —OCH3, —OCH2CH3, —CN, —NH2, —NHCH3, —N(CH3)2, —C(═O)NH(CH3), or —NHC(═O)CH3. In still others, the benzoxazolyl is substituted with one or more —CH3, —CH(CH3)2, —F or —OCH2CH3.
In other embodiments of compounds of formula (I), R3 is substituted or unsubstituted aryl, for example, R3 is substituted or unsubstituted phenyl. In some such embodiments, the phenyl is substituted with one or more substituents selected from substituted or unsubstituted C1-4 alkyl, halogen, —CN, —OR, —NR2, —NRSO2R′, —NR(C═O)NR2, —NR(C═O)R′, —COOR, —(C═O)NR2, —C(═NH)NR2, —SO2R′, or substituted or unsubstituted heteroaryl, wherein each R is independently —H or substituted or unsubstituted (C1-4)alkyl, and R′ is C1-3 alkyl. In yet other embodiments, the phenyl is substituted with one or more substituents selected from —CH3, —CH2OH, —CH(OH)CH3, —C(CH3)2OH, —CN, —F, —Cl, —OH, —OCH3, —NH2, —N(CH3)2, —NHSO2CH3, —NH(C═O)NH2, —NH(C═O)CH3, —COOCH3, —(C═O)NHCH3, —C(═N)NH2, —SO2CH3, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazolyl, or substituted or unsubstituted imidazolyl.
In some such embodiments of R3, R1 is substituted or unsubstituted C1-8 alkyl,
Figure US09623028-20170418-C00015
wherein
each R′ is independently —OR or C1-3 alkyl;
R″ is —H or C1-3 alkyl;
each R is independently —H or substituted or unsubstituted (C1-4)alkyl; and
n is 0-2.
In some such embodiments, R2 is phenyl, substituted with one or more —(C1-3 alkyl), —(C1-3 alkyl)NR2, —CF3, —Cl, —F, —CN, —OCH3, —OCF3, —C(═O)NR2, —C(═O)NR (substituted or unsubstituted cycloalkyl), —C(═O)NR(CH2)0-2CR2(CH2)0-2OR, —C(═O)NR(CH2)0-2CR2(CH2)0-2NR2, —C(═O)NR(CH2)0-2CR2(CH2)0-2C(═O)NR2, —C(═O)N (substituted or unsubstituted cycloalkyl)(CH2)0-2OR, —C(═O)NR(CH2)0-3 (substituted or unsubstituted heterocyclyl), —C(═O)(CH2)0-3 (substituted or unsubstituted heterocyclyl), —C(═NR)NR2, —NRC(═O)R, —SO2NR2, —SO2R, or substituted or unsubstituted heterocyclyl, wherein each R is independently —H or substituted or unsubstituted (C1-4)alkyl.
Further embodiments provided herein include combinations of one or more of the particular embodiments set forth above.
In some embodiments of compounds of formula (I), the compound is selected from Table A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or isotopologue thereof.
Pyrrolopyrimidine Compounds set forth in Table A were tested in the assays described herein and were found to have activity as cancer treatment agents, in particular for the treatment of solid tumors and hematological cancers as described herein. In some embodiments, the solid tumor is bladder cancer (including superficial bladder cancer), breast cancer (including luminal B type, ER+, PR+ and Her2+ breast cancer), central nervous system cancer (including glioblastoma multiforme (GBM), glioma, medulloblastoma, and astrocytoma), colorectal cancer, gastrointestinal cancer (including stomach cancer, oesophagus cancer, and rectum cancer), endocrine cancer (including thyroid cancer, and adrenal gland cancer), eye cancer (including retinoblastoma), female genitourinary cancer (including cancer of the placenta, uterus, vulva, ovary, cervix), head and neck cancer (including cancer of the pharynx, oesophagus, and tongue), liver cancer, lung cancer (including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), mucoepidermoid, bronchogenic, squamous cell carcinoma (SQCC), and analplastic/NSCLC), skin cancer (including melanoma, and SQCC), soft tissue cancer (including sarcoma, Ewing's sarcoma, and rhabdomyosarcoma), bone cancer (including sarcoma, Ewing's sarcoma, and osteosarcoma), squamous cell cancer (including lung, esophageal, cervical, and head and neck cancer), pancreas cancer, kidney cancer (including renal Wilm's tumor and renal cell carcinoma), or prostate cancer. In some embodiments, the solid tumor is breast cancer, colon cancer, lung cancer or bladder cancer. In one such embodiment, the solid tumor is superficial bladder cancer. In another, the solid tumor is lung squamous cell carcinoma. In yet another embodiment, the solid tumor is luminal B type breast cancer.
In some embodiments, the hematological cancer is leukemia (including acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), acute T-cell leukemia, B cell precursor leukemia, acute promyelocytic leukemia (APML), plasma cell leukemia, myelomonoblastic/T-ALL, B myelomonocytic leukemia, erythroleukemia, and acute myeloid leukemia (AML)), lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), B cell lymphoma, lymphoblastic lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and large cell immunoblastic lymphoma), or multiple myeloma.
In one embodiment, the Pyrrolopyrimidine Compound is a compound as described herein, wherein the compound at a concentration of 10 μM inhibits cancer cell proliferation, for example solid tumor or hematological cancer cell proliferation, as described herein, by at least about 50% or more.
TABLE A
Cmpd
No. Structure Name
1
Figure US09623028-20170418-C00016
 		4-(4-(cyclopentyloxy)-5-(4- hydroxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N- methylbenzamide
2
Figure US09623028-20170418-C00017
 		4-(4-(cyclopentyloxy)-5-(3- hydroxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N- methylbenzamide
3
Figure US09623028-20170418-C00018
 		4-(4-(cyclopentyloxy)-5-(4- hydroxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
4
Figure US09623028-20170418-C00019
 		4-(5-(4-hydroxyphenyl)-4- methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N- methylbenzamide
5
Figure US09623028-20170418-C00020
 		4-(2-(1H-indazol-5-ylamino)-4- (cyclohexyloxy)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)phenol
6
Figure US09623028-20170418-C00021
 		4-(2-(4-(1H-pyrazol-4- yl)phenylamino)-4- (cyclohexyloxy)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)phenol
7
Figure US09623028-20170418-C00022
 		4-(5-(2-chloro-4-hydroxyphenyl)- 4-(cyclohexyloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
8
Figure US09623028-20170418-C00023
 		4-(2-(3-(1H-pyrazol-4- yl)phenylamino)-4- (cyclohexyloxy)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)phenol
9
Figure US09623028-20170418-C00024
 		4-(4-(cyclopentyloxy)-5-(4- hydroxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N,3- diethylbenzamide
10
Figure US09623028-20170418-C00025
 		4-(4-(cyclopentyloxy)-5-(4- hydroxyhenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3-ethyl- N-methylbenzamide
11
Figure US09623028-20170418-C00026
 		4-(4-(cyclopentyloxy)-5-(4- hydroxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- isopropyl-N-methylbenzamide
12
Figure US09623028-20170418-C00027
 		4-(4-(cyclopentyloxy)-5-(4- fluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
13
Figure US09623028-20170418-C00028
 		4-(4-(cyclopentyloxy)-5-phenyl- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
14
Figure US09623028-20170418-C00029
 		3-chloro-4-(4-(cyclopentyloxy)-5- (4-hydroxyphenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
15
Figure US09623028-20170418-C00030
 		4-(4-(cyclopentyloxy)-5-(4- hydroxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3-fluoro- N-methylbenzamide
16
Figure US09623028-20170418-C00031
 		4-(4-(cyclopentylamino)-5-(4- hydroxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
17
Figure US09623028-20170418-C00032
 		4-(5-(4-hydroxyphenyl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
18
Figure US09623028-20170418-C00033
 		4-(5-(4-hydroxyphenyl)-4- (neopentyloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
19
Figure US09623028-20170418-C00034
 		4-(5-(4-hydroxyphenyl)-4- methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
20
Figure US09623028-20170418-C00035
 		4-(4-(cyclopentyloxy)-2-(1- methyl-1H-indazol-5-ylamino)- 7H-pyrrolo[2,3-d]pyrimidin-5- yl)phenol
21
Figure US09623028-20170418-C00036
 		4-(4-(cyclopentyloxy)-2-(6- methyl-1H-indazol-5-ylamino)- 7H-pyrrolo[2,3-d]pyrimidin-5- yl)phenol
22
Figure US09623028-20170418-C00037
 		4-(4-(cyclopentyloxy)-2-(4- methyl-1H-indazol-5-ylamino)- 7H-pyrrolo[2,3-d]pyrimidin-5- yl)phenol
23
Figure US09623028-20170418-C00038
 		4-(4-(cyclopentyloxy)-5-(4- (hydroxymethyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
24
Figure US09623028-20170418-C00039
 		4-(5-(3-chloro-4-hydroxyphenyl)- 4-(cyclopentyloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
25
Figure US09623028-20170418-C00040
 		4-(4-(cyclopentyloxy)-5-(1H- indazol-6-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
26
Figure US09623028-20170418-C00041
 		4-(4-(cyclopentyloxy)-5-(3- (hydroxymethyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
27
Figure US09623028-20170418-C00042
 		4-(5-(1H-benzo[d][1,2,3]triazol- 6-yl)-4-(cyclopentyloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
28
Figure US09623028-20170418-C00043
 		4-(5-(4-(4H-1,2,4-triazol-3- yl)phenyl)-4-(cyclopentyloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
29
Figure US09623028-20170418-C00044
 		3-chloro-4-(5-(4-hydroxyphenyl)- 4-(tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
30
Figure US09623028-20170418-C00045
 		4-(5-(1H-benzo[d]imidazol-6-yl)- 4-(cyclopentyloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
31
Figure US09623028-20170418-C00046
 		4-(4-(cyclopentyloxy)-5-(4- hydroxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N,N- dimethylbenzamide
32
Figure US09623028-20170418-C00047
 		4-(4-(cyclopentyloxy)-5-(4- (methylsulfonamido)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
33
Figure US09623028-20170418-C00048
 		4-(5-(3-cyano-4-hydroxyphenyl)- 4-(cyclopentyloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
34
Figure US09623028-20170418-C00049
 		3-chloro-4-(4-(cyclopentyloxy)-5- (5-methoxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
35
Figure US09623028-20170418-C00050
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
36
Figure US09623028-20170418-C00051
 		4-(4-(cyclohexylamino)-5-(4- hydroxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
37
Figure US09623028-20170418-C00052
 		4-(5-(aminophenyl)-4- (cyclopentyloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
38
Figure US09623028-20170418-C00053
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
39
Figure US09623028-20170418-C00054
 		4-(4-(cyclopentyloxy)-5-(4- ureidophenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
40
Figure US09623028-20170418-C00055
 		4-(5-(4-hydroxyphenyl)-4- (tetrahydro-2H-pyran-4-ylamino)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
41
Figure US09623028-20170418-C00056
 		4-(5-(4-(1H-pyrazol-5-yl)phenyl)- 4-(cyclopentyloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
42
Figure US09623028-20170418-C00057
 		4-(4-(cyclopentyloxy)-5-(3- fluoro-4-hydroxyphenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
43
Figure US09623028-20170418-C00058
 		4-(4-(cyclopentyloxy)-5-(4- hydroxy-3-methylphenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
44
Figure US09623028-20170418-C00059
 		4-(4-(cyclopentyloxy)-5-(4- hydroxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxybenzamide
45
Figure US09623028-20170418-C00060
 		4-(4-((1r,4r)-4- hydroxycyclohexyloxy)-5-(4- hydroxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
46
Figure US09623028-20170418-C00061
 		4-(4-((1s,4s)-4- hydroxycyclohexyloxy)-5-(4- hydroxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
47
Figure US09623028-20170418-C00062
 		4-(4-(cyclopentyloxy)-5-(3-(2- hydroxypropan-2-yl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
48
Figure US09623028-20170418-C00063
 		4-(5-(4-(1H-imidazol-2- yl)phenyl)-4-(cyclopentyloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
49
Figure US09623028-20170418-C00064
 		4-(4-(cyclopentyloxy)-5-(4-(2- hydroxypropan-2-yl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
50
Figure US09623028-20170418-C00065
 		4-(4-(cyclopentyloxy)-2-(2- methoxy-4-(1H-pyrazol-4- yl)phenylamino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)phenol
51
Figure US09623028-20170418-C00066
 		4-(4-(cyclopentyloxy)-5-(5- hydroxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
52
Figure US09623028-20170418-C00067
 		4-(2-(4-(aminomethyl)-2- methoxyphenylamino)-4- (cyclopentyloxy)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)phenol
53
Figure US09623028-20170418-C00068
 		4-(5-(4-(4H-1,2,4-triazol-3- yl)phenyl)-4-methoxy-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-chloro-N,N- dimethylbenzamide
54
Figure US09623028-20170418-C00069
 		4-(4-(cyclopentyloxy)-5-(3- fluoro-4-methoxyphenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
55
Figure US09623028-20170418-C00070
 		4-(4-(cyclopentyloxy)-5-(6- methoxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
56
Figure US09623028-20170418-C00071
 		4-(5-(3-acetamidophenyl)-4- (cyclopentyloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
57
Figure US09623028-20170418-C00072
 		4-(4-(cyclopentyloxy)-5-(3- (methylsulfonamido)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
58
Figure US09623028-20170418-C00073
 		4-(4-(cyclopentyloxy)-5-(pyridin- 3-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
59
Figure US09623028-20170418-C00074
 		4-(4-(cyclopentyloxy)-5-(3- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
60
Figure US09623028-20170418-C00075
 		4-(4-(cyclopentyloxy)-5-(3- methoxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
61
Figure US09623028-20170418-C00076
 		4-(4-(cyclopentyloxy)-5-(4- (methylsulfonyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
62
Figure US09623028-20170418-C00077
 		4-(5-(4-acetamidophenyl)-4- (cyclopentyloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
63
Figure US09623028-20170418-C00078
 		4-(4-(cyclopentyloxy)-5-(3- (methylsulfonyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
64
Figure US09623028-20170418-C00079
 		4-(4-(cyclopentyloxy)-5-(3,4- dimethoxyphenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
65
Figure US09623028-20170418-C00080
 		4-(5-(3-aminophenyl)-4- (cyclopentyloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
66
Figure US09623028-20170418-C00081
 		4-(4-(cyclopentyloxy)-5-(pyridin- 4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
67
Figure US09623028-20170418-C00082
 		4-(4-(cyclopentyloxy)-5-(6- ethoxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
68
Figure US09623028-20170418-C00083
 		(4-(5-(4-(4H-1,2,4-triazol-3- yl)phenyl)-4-methoxy-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3- chlorophenyl)(morpholino)- methanone
69
Figure US09623028-20170418-C00084
 		N,N,3-trimethyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-ylamino)- 7H-pyrrolo[2,3-dpyrimidin-2- ylamino)benzamide
70
Figure US09623028-20170418-C00085
 		N,N,3-trimethyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
71
Figure US09623028-20170418-C00086
 		4-(5-(2-amino-1H- benzo[d]imidazol-5-yl)-4- methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3-chloro- N,N-dimethylbenzamide
72
Figure US09623028-20170418-C00087
 		4-(5-(4-(4H-1,2,4-triazol-3- yl)phenyl)-4-(methylamino)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-chloro-N,N- dimethylbenzamide
73
Figure US09623028-20170418-C00088
 		4-(4-methoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N,3- trimethylbenzamide
74
Figure US09623028-20170418-C00089
 		(3-methyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-ylamino)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)phenyl)(piperazin-1- yl)methanone
75
Figure US09623028-20170418-C00090
 		4-(4-(cyclopentyloxy)-5-(4- (dimethylamino)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
76
Figure US09623028-20170418-C00091
 		4-(4-(cyclopentyloxy)-5-(4- methoxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
77
Figure US09623028-20170418-C00092
 		4-(5-(4-cyanophenyl)-4- (cyclopentyloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
78
Figure US09623028-20170418-C00093
 		4-(4-(cyclopentyloxy)-5-(1- methyl-1H-indol-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
79
Figure US09623028-20170418-C00094
 		4-(4-(cyclopentyloxy)-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
80
Figure US09623028-20170418-C00095
 		4-(4-(cyclopentyloxy)-5-(1H- pyrazol-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
81
Figure US09623028-20170418-C00096
 		4-(4-(cyclopentyloxy)-5-(1H- indol-5-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
82
Figure US09623028-20170418-C00097
 		4-(4-(cyclopentyloxy)-5-(1H- pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
83
Figure US09623028-20170418-C00098
 		3-chloro-4-(4-methoxy-5-(2- methyl-1H-benzo[d]imidazol-5- yl)-7H-pyrrolo[2,3-d]pyrimidin- 2-ylamino)-N,N- dimethylbenzamide
84
Figure US09623028-20170418-C00099
 		(R)-3-chloro-4-(5-(3-(1- hydroxyethyl)phenyl)-4- (tetrahydro-2H-pyran-4-ylamino)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N- dimethylbenzamide
85
Figure US09623028-20170418-C00100
 		(S)-3-chloro-4-(5-(3-(1- hydroxyethyl)phenyl)-4- (tetrahydro-2H-pyran-4-ylamino)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N- dimethylbenzamide
86
Figure US09623028-20170418-C00101
 		(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3- methylphenyl)(morpholino) methanone
87
Figure US09623028-20170418-C00102
 		N-(1H-indazol-5-yl)-4-methoxy- 5-(2-methylbenzo[d]oxazol-6-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- amine
88
Figure US09623028-20170418-C00103
 		N-(4-(1H-pyrazol-4-yl)phenyl)-4- methoxy-5-(2-methylbenzo[d] oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine
89
Figure US09623028-20170418-C00104
 		4-(4-methoxy-5-(pyridin-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N,3- trimethylbenzamide
90
Figure US09623028-20170418-C00105
 		3-methoxy-N-methyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
91
Figure US09623028-20170418-C00106
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N,N- dimethylbenzamide
92
Figure US09623028-20170418-C00107
 		4-(4-((1r,4r)-4- hydroxycyclohexyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N,3- trimethylbenzamide
93
Figure US09623028-20170418-C00108
 		N,N,3-trimethyl-4-(5-(pyridin-4- yl)-4-(tetrahydro-2H-pyran-4- yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2- ylamino)benzamide
94
Figure US09623028-20170418-C00109
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,3-dimethylbenzamide
95
Figure US09623028-20170418-C00110
 		N,N,3-trimethyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4-(1- methylpiperidin-4-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
96
Figure US09623028-20170418-C00111
 		(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxyphenyl) (morpholino)methanone
97
Figure US09623028-20170418-C00112
 		N,N,3-trimethyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (piperidin-4-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
98
Figure US09623028-20170418-C00113
 		(S)-N,N,3-trimethyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
99
Figure US09623028-20170418-C00114
 		(R)-N,N,3-trimethyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
100
Figure US09623028-20170418-C00115
 		N-(2-aminoethyl)-4-(4- (cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxybenzamide
101
Figure US09623028-20170418-C00116
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(2-hydroxyethyl)-3- methoxybenzamide
102
Figure US09623028-20170418-C00117
 		4-(5-(6-ethoxypyridin-3-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
103
Figure US09623028-20170418-C00118
 		4-(cyclopentyloxy)-N-(2- methoxyphenyl)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine
104
Figure US09623028-20170418-C00119
 		(S)-N,N,3-trimethyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-3-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
105
Figure US09623028-20170418-C00120
 		N,N,3-trimethyl-4-(5-(3- (methylsulfonyl)phenyl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
106
Figure US09623028-20170418-C00121
 		3-methoxy-N-methyl-4-(5-(3- (methylsulfonyl)phenyl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
107
Figure US09623028-20170418-C00122
 		N,N,3-trimethyl-4-(5-(pyrimidin- 5-yl)-4-(tetrahydro-2H-pyran-4- yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2- ylamino)benzamide
108
Figure US09623028-20170418-C00123
 		3-methoxy-N-methyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-ylamino)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
109
Figure US09623028-20170418-C00124
 		4-(5-(6-ethoxypyridin-3-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N,3- trimethylbenzamide
110
Figure US09623028-20170418-C00125
 		4-(5-(2-amino-1H- benzo[d]imidazol-6-yl)-4- (cyclopentyloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
111
Figure US09623028-20170418-C00126
 		4-(5-(1,3,4-oxadiazol-2-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N,3- trimethylbenzamide
112
Figure US09623028-20170418-C00127
 		N,N,3-trimethyl-4-(5-(1-methyl- 1H-pyrazol-4-yl)-4-(tetrahydro- 2H-pyran-4-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
113
Figure US09623028-20170418-C00128
 		N,N,3-trimethyl-4-(5-(1-methyl- 1H-pyrazol-3-yl)-4-(tetrahydro- 2H-pyran-4-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
114
Figure US09623028-20170418-C00129
 		3-methoxy-N-methyl-4-(5- (pyridin-4-yl)-4-(tetrahydro-2H- pyran-4-yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2- ylamino)benzamide
115
Figure US09623028-20170418-C00130
 		N,N,3-trimethyl-4-(5-(oxazol-2- yl)-4-(tetrahydro-2H-pyran-4- yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2- ylamino)benzamide
116
Figure US09623028-20170418-C00131
 		4-(5-(2-amino-1H- benzo[d]imidazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N,3- trimethylbenzamide
117
Figure US09623028-20170418-C00132
 		N,N,3-trimethyl-4-(5-(2- methylpyridin-4-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
118
Figure US09623028-20170418-C00133
 		3-methoxy-4-(4-methoxy-5-(6- methoxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
119
Figure US09623028-20170418-C00134
 		3-methoxy-4-(5-(6- methoxypyridin-3-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
120
Figure US09623028-20170418-C00135
 		3-methoxy-N-(2-methoxyethyl)- 4-(5-(2-methylbenzo[d]oxazol-6- yl)-4-(tetrahydro-2H-pyran-4- yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2- ylamino)benzamide
121
Figure US09623028-20170418-C00136
 		(R)-N,N,3-trimethyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-3-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
122
Figure US09623028-20170418-C00137
 		4-(5-(1H-pyrazol-4-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
123
Figure US09623028-20170418-C00138
 		3-methoxy-N-methyl-4-(5-(4- (methylcarbamoyl)phenyl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
124
Figure US09623028-20170418-C00139
 		3-methoxy-4-(4-methoxy-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
125
Figure US09623028-20170418-C00140
 		4-(4-isopropoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
126
Figure US09623028-20170418-C00141
 		4-(5-(6-(dimethylamino)pyridin- 3-yl)-4-(tetrahydro-2H-pyran-4- yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
127
Figure US09623028-20170418-C00142
 		N-(2-(dimethylamino)ethyl)-3- methoxy-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
128
Figure US09623028-20170418-C00143
 		N,N,3-trimethyl-4-(5-(2-methyl- 1H-benzo[d]imidazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
129
Figure US09623028-20170418-C00144
 		3-methoxy-4-(4-methoxy-5-(1H- pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N- methylbenzamide
130
Figure US09623028-20170418-C00145
 		3-methoxy-N-(2- (methylamino)ethyl)-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
131
Figure US09623028-20170418-C00146
 		4-(5-(2-(dimethylamino)pyridin- 4-yl)-4-(tetrahydro-2H-pyran-4- yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
132
Figure US09623028-20170418-C00147
 		3-chloro-N-methyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
133
Figure US09623028-20170418-C00148
 		(S)-N,3-dimethyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
134
Figure US09623028-20170418-C00149
 		(S)-3-chloro-N-methyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
135
Figure US09623028-20170418-C00150
 		4-(5-(2,7- dimethylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
136
Figure US09623028-20170418-C00151
 		4-(5-(2,5- dimethylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
137
Figure US09623028-20170418-C00152
 		4-(4-((1r,4r)-4- hydroxycyclohexyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
138
Figure US09623028-20170418-C00153
 		3-methoxy-N-methyl-4-(4-(2- (methylamino)ethoxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
139
Figure US09623028-20170418-C00154
 		3-methoxy-4-(4-(2- methoxyethoxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
140
Figure US09623028-20170418-C00155
 		4-(5-(2-cyanopyridin-4-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N,3- trimethylbenzamide
141
Figure US09623028-20170418-C00156
 		4-(5-(4-(1H-imidazol-2- yl)phenyl)-4-methoxy-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
142
Figure US09623028-20170418-C00157
 		4-(5-(2-aminopyridin-4-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
143
Figure US09623028-20170418-C00158
 		3-methoxy-4-(5-(2- methoxypyridin-4-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
144
Figure US09623028-20170418-C00159
 		N,3-dimethyl-4-(5-(3- (methylcarbamoyl)phenyl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
145
Figure US09623028-20170418-C00160
 		N,3-dimethyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
146
Figure US09623028-20170418-C00161
 		4-(5-(4-(1H-imidazol-2- yl)phenyl)-4-(tetrahydro-2H- pyran-4-yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
147
Figure US09623028-20170418-C00162
 		4-(5-(2-hydroxypyridin-4-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
148
Figure US09623028-20170418-C00163
 		4-(5-(1,2-dimethyl-1H- benzo[d]imidazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
149
Figure US09623028-20170418-C00164
 		4-(4-methoxy-5-(3- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,3-dimethylbenzamide
150
Figure US09623028-20170418-C00165
 		4-(4-((1r,4r)-4-hydroxy-4- methylcyclohexyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,3-dimethylbenzamide
151
Figure US09623028-20170418-C00166
 		4-(4-((1s,4s)-4-hydroxy-4- methylcyclohexyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,3-dimethylbenzamide
152
Figure US09623028-20170418-C00167
 		4-(4-cyclopropoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
153
Figure US09623028-20170418-C00168
 		(S)-N,3-dimethyl-4-(5-(4- (methylcarbamoyl)phenyl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2 ylamino)benzamide
154
Figure US09623028-20170418-C00169
 		3-methoxy-N-methyl-4-(5- (pyrimidin-5-yl)-4-(tetrahydro- 2H-pyran-4-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
155
Figure US09623028-20170418-C00170
 		3-methoxy-N-methyl-4-(5-(2- (methylamino)pyridin-4-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
156
Figure US09623028-20170418-C00171
 		4-(4-methoxy-5-(pyridin-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,3-dimethylbenzamide
157
Figure US09623028-20170418-C00172
 		3-chloro-4-(4-methoxy-5- (pyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N,N- dimethylbenzamide
158
Figure US09623028-20170418-C00173
 		N,3-dimethyl-4-(5-(4- (methylsulfonyl)phenyl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
159
Figure US09623028-20170418-C00174
 		5-(2-(4-(dimethylcarbamoyl)-2- methylphenylamino)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-5- yl)-N-methylpicolinamide
160
Figure US09623028-20170418-C00175
 		N-(2-hydroxyethyl)-4-(4- isopropoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxybenzamide
161
Figure US09623028-20170418-C00176
 		(S)-4-(5-(6-ethoxypyridin-3-yl)- 4-(tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
162
Figure US09623028-20170418-C00177
 		(S)-4-(5-(6-ethoxypyridin-3-yl)- 4-(tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,3-dimethylbenzamide
163
Figure US09623028-20170418-C00178
 		3-methoxy-N-methyl-4-(5-(1- methyl-1H-pyrazol-3-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
164
Figure US09623028-20170418-C00179
 		(S)-N,N,3-trimethyl-4-(5-(1- methyl-1H-pyrazol-4-yl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
165
Figure US09623028-20170418-C00180
 		(S)-N,3-dimethyl-4-(5-(1-methyl- 1H-pyrazol-4-yl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
166
Figure US09623028-20170418-C00181
 		3-methoxy-4-(4-methoxy-5-(2- methylpyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
167
Figure US09623028-20170418-C00182
 		3-methoxy-N-methyl-4-(5-(2- methylpyridin-4-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
168
Figure US09623028-20170418-C00183
 		4-(4-(2-hydroxyethoxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
169
Figure US09623028-20170418-C00184
 		(S)-3-methoxy-N-methyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
170
Figure US09623028-20170418-C00185
 		4-(5-(2-isopropylbenzo[d]oxazol- 6-yl)-4-(tetrahydro-2H-pyran-4- yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
171
Figure US09623028-20170418-C00186
 		3-cyano-N-methyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
172
Figure US09623028-20170418-C00187
 		3-methoxy-N-methyl-4-(5-(1- methyl-1H-imidazol-2-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
173
Figure US09623028-20170418-C00188
 		3-methoxy-N-methyl-4-(5- (oxazol-2-yl)-4-(tetrahydro-2H- pyran-4-yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2- ylamino)benzamide
174
Figure US09623028-20170418-C00189
 		4-(5-(1,3,4-oxadiazol-2-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
175
Figure US09623028-20170418-C00190
 		(S)-4-(5-(3-(1- hydroxyethyl)phenyl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
176
Figure US09623028-20170418-C00191
 		(S)-N,N,3-trimethyl-4-(5- (pyridin-4-yl)-4-(tetrahydrofuran- 3-yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2- ylamino)benzamide
177
Figure US09623028-20170418-C00192
 		3-methoxy-4-(4-methoxy-5-(1- methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
178
Figure US09623028-20170418-C00193
 		(S)-3-methoxy-N-methyl-4-(5-(2- methylpyridin-4-yl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
179
Figure US09623028-20170418-C00194
 		3-methoxy-N-methyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (oxetan-3-yloxy)-7H-pyrrlo[2,3- d]pyrimidin-2- ylamino)benzamide
180
Figure US09623028-20170418-C00195
 		3-(4-isopropoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-4-methoxy-N- methylbenzamide
181
Figure US09623028-20170418-C00196
 		4-methoxy-N-methyl-3-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
182
Figure US09623028-20170418-C00197
 		(S)-3-methoxy-N-methyl-4-(5-(4- (methylcarbamoyl)phenyl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
183
Figure US09623028-20170418-C00198
 		6-methoxy-N-methyl-5-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)picolinamide
184
Figure US09623028-20170418-C00199
 		3-methoxy-N-methyl-4-(5-(1- methyl-1H-pyrazol-4-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
185
Figure US09623028-20170418-C00200
 		4-(4-isopropoxy-5-(2- methoxypyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
186
Figure US09623028-20170418-C00201
 		3-methoxy-N-methyl-4-(5- (pyrazin-2-yl)-4-(tetrahydro-2H- pyran-4-yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2- ylamino)benzamide
187
Figure US09623028-20170418-C00202
 		4-(4-isopropoxy-5-(3- (methylsulfonyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
188
Figure US09623028-20170418-C00203
 		4-(4-isopropoxy-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
189
Figure US09623028-20170418-C00204
 		4-(4-isopropoxy-5-(1-methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
190
Figure US09623028-20170418-C00205
 		3-methoxy-4-(4-methoxy-5- (pyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N- methylbenzamide
191
Figure US09623028-20170418-C00206
 		N-methyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3- (trifluoromethyl)benzamide
192
Figure US09623028-20170418-C00207
 		N-methyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3- (trifluoromethoxy)benzamide
193
Figure US09623028-20170418-C00208
 		4-(5-(4-(1H-imidazol-2- yl)phenyl)-4-isopropoxy-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
194
Figure US09623028-20170418-C00209
 		4-(5-(2-aminopyridin-4-yl)-4- isopropoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
195
Figure US09623028-20170418-C00210
 		3-methoxy-N-methyl-4-(5-(4-(1- methyl-1H-imidazol-2- yl)phenyl)-4-(tetrahydro-2H- pyran-4-yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2- ylamino)benzamide
196
Figure US09623028-20170418-C00211
 		4-(5-(6-ethoxypyridin-3-yl)-4- isopropoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
197
Figure US09623028-20170418-C00212
 		4-(5-(4-(4,5-dimethyl-1H- imidazol-2-yl)phenyl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
198
Figure US09623028-20170418-C00213
 		4-(4-cyclobutoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
199
Figure US09623028-20170418-C00214
 		4-(4-isopropoxy-5-(2- (methylamino)pyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
200
Figure US09623028-20170418-C00215
 		3-isopropyl-N-methyl-4-(5- (pyridin-4-yl)-4-(tetrahydro-2H- pyran-4-yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2- ylamino)benzamide
201
Figure US09623028-20170418-C00216
 		4-(4-isopropoxy-5-(2- methylpyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
202
Figure US09623028-20170418-C00217
 		4-(4-(isopropylamino)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
203
Figure US09623028-20170418-C00218
 		(R)-4-(4-sec-butoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
204
Figure US09623028-20170418-C00219
 		(S)-4-(4-sec-butoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
205
Figure US09623028-20170418-C00220
 		4-(4-((1r,4r)-4-hydroxy-4- methylcyclohexyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
206
Figure US09623028-20170418-C00221
 		4-(4-((1s,4s)-4-hydroxy-4- methylcyclohexyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
207
Figure US09623028-20170418-C00222
 		3-methoxy-N-methyl-4-(5-(4-(4- methyl-1H-imidazol-2- yl)phenyl)-4-(tetrahydro-2H- pyran-4-yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2- ylamino)benzamide
208
Figure US09623028-20170418-C00223
 		(S)-3-isopropyl-N-methyl-4-(5- (1-methyl-1H-pyrazol-4-yl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
209
Figure US09623028-20170418-C00224
 		(S)-3-isopropyl-N-methyl-4-(5- (2-methylbenzo[d]oxazol-6-yl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
210
Figure US09623028-20170418-C00225
 		3-methoxy-N-methyl-4-(5-(1- methyl-1H-pyrazol-4-yl)-4- (tetrahydro-2H-pyran-4-ylamino)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
211
Figure US09623028-20170418-C00226
 		4-(4-(cyclopropylamino)-5-(1- methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
212
Figure US09623028-20170418-C00227
 		4-(4-(cyclopropylamino)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
213
Figure US09623028-20170418-C00228
 		N-(2-hydroxyethyl)-3-methoxy-4- (5-(2-methylbenzo[d]oxazol-6- yl)-4-(tetrahydro-2H-pyran-4- yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2- ylamino)benzamide
214
Figure US09623028-20170418-C00229
 		(R)-4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(1-hydroxypropan-2- yl)-3-methoxybenzamide
215
Figure US09623028-20170418-C00230
 		(S)-4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(1-hydroxypropan-2- yl)-3-methoxybenzamide
216
Figure US09623028-20170418-C00231
 		4-(4-cyclopropoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(2-hydroxyethyl)-3- methoxybenzamide
217
Figure US09623028-20170418-C00232
 		4-(4-cyclopropoxy-5-(1-methyl- 1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N-(2- hydroxyethyl)-3- methoxybenzamide
218
Figure US09623028-20170418-C00233
 		4-(4-cyclopropoxy-5-(1-methyl- 1H-pyrazol-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
219
Figure US09623028-20170418-C00234
 		3-methoxy-N-methyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzenesulfonamide
220
Figure US09623028-20170418-C00235
 		4-(4-isopropoxy-5-(1-methyl-1H- pyrazol-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
221
Figure US09623028-20170418-C00236
 		3-methoxy-4-(4-(2- methoxyethoxy)-5-(1-methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N,N- dimethylbenzamide
222
Figure US09623028-20170418-C00237
 		(R)-3-methoxy-N,N-dimethyl-4- (5-(2-methylbenzo[d]oxazol-6- yl)-4-(tetrahydrofuran-3-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
223
Figure US09623028-20170418-C00238
 		3-methoxy-N-methyl-4-(5-(2- methylbenzo[d]thiazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
224
Figure US09623028-20170418-C00239
 		N-tert-butyl-4-(4- (cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxybenzamide
225
Figure US09623028-20170418-C00240
 		(S)-3-isopropyl-N-methyl-4-(5- (1-methyl-1H-pyrazol-5-yl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
226
Figure US09623028-20170418-C00241
 		4-(4-isopropoxy-5-(1-methyl-1H- pyrazol-5-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
227
Figure US09623028-20170418-C00242
 		4-(cyclopentyloxy)-N-(2- methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine
228
Figure US09623028-20170418-C00243
 		4-(cyclopentyloxy)-N-(2- methoxy-4-(1H-pyrazol-1- yl)phenyl)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine
229
Figure US09623028-20170418-C00244
 		N-cyclopentyl-4-(4- (cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxybenzamide
230
Figure US09623028-20170418-C00245
 		(R)-4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(2-hydroxypropyl)-3- methoxybenzamide
231
Figure US09623028-20170418-C00246
 		(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxyphenyl)(4- hydroxypiperidin-1-yl)methanone
232
Figure US09623028-20170418-C00247
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(3-hydroxypropyl)-3- methoxybenzamide
233
Figure US09623028-20170418-C00248
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(2-hydroxyethyl)-3- methoxy-N-methylbenzamide
234
Figure US09623028-20170418-C00249
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(1-hydroxy-2- methylpropan-2-yl)-3- methoxybenzamide
235
Figure US09623028-20170418-C00250
 		5-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)isoindolin-1-one
236
Figure US09623028-20170418-C00251
 		4-(5-(2-acetamidopyridin-4-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
237
Figure US09623028-20170418-C00252
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-2-fluoro-5-methoxy-N- methylbenzamide
238
Figure US09623028-20170418-C00253
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-((1s,3s)-3- hydroxycyclobutyl)-3- methoxybenzamide
239
Figure US09623028-20170418-C00254
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-((1r,3r)-3- hydroxycyclobutyl)-3- methoxybenzamide
240
Figure US09623028-20170418-C00255
 		(S)-4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(2-hydroxypropyl)-3- methoxybenzamide
241
Figure US09623028-20170418-C00256
 		azetidin-1-yl(4-(4- (cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3- methoxyphenyl)methanone
242
Figure US09623028-20170418-C00257
 		(R)-4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- ((tetrahydrofuran-2- yl)methyl)benzamide
243
Figure US09623028-20170418-C00258
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- ((tetrahydro-2H-pyran-4- yl)methyl)benzamide
244
Figure US09623028-20170418-C00259
 		5-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-2-methylisoindolin-1- one
245
Figure US09623028-20170418-C00260
 		4-(5-(4-carbamimidoylphenyl)-4- (cyclopentyloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
246
Figure US09623028-20170418-C00261
 		4-(4-tert-butoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
247
Figure US09623028-20170418-C00262
 		N-(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3- methoxyphenyl)acetamide
248
Figure US09623028-20170418-C00263
 		N-(2-cyanoethyl)-4-(4- (cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
249
Figure US09623028-20170418-C00264
 		(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3- methoxyphenyl)(pyrrolidin-1- yl)methanone
250
Figure US09623028-20170418-C00265
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-methyl- N-(tetrahydro-2H-pyran-4- yl)benzamide
251
Figure US09623028-20170418-C00266
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-cyclopropyl-N-(2- hydroxyethyl)-3- methoxybenzamide
252
Figure US09623028-20170418-C00267
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- (tetrahydro-2H-pyran-4- yl)benzamide
253
Figure US09623028-20170418-C00268
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-((1R,2S)-2- hydroxycyclopentyl)-3- methoxybenzamide
254
Figure US09623028-20170418-C00269
 		(S)-4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- ((tetrahydrofuran-2- yl)methyl)benzamide
255
Figure US09623028-20170418-C00270
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
256
Figure US09623028-20170418-C00271
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(2-fluoroethyl)-3- methoxybenzamide
257
Figure US09623028-20170418-C00272
 		N-(3-amino-3-oxopropyl)-4-(4- (cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
258
Figure US09623028-20170418-C00273
 		4-(4-(cyclopentyloxy)-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(2-hydroxyethyl)-3- methoxybenzamide
259
Figure US09623028-20170418-C00274
 		(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxyphenyl)(4- methylpiperazin-1-yl)methanone
260
Figure US09623028-20170418-C00275
 		4-(5-(benzo[c][1,2,5]oxadiazol-5- yl)-4-(cyclopentyloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
261
Figure US09623028-20170418-C00276
 		4-(cyclopentyloxy)-N-(5-fluoro- 2-methoxy-4- (methylsulfonyl)phenyl)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine
262
Figure US09623028-20170418-C00277
 		aziridin-1-yl(4-(4- (cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3- methoxyphenyl)methanone
263
Figure US09623028-20170418-C00278
 		N-(cyanomethyl)-4-(4- (cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
264
Figure US09623028-20170418-C00279
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-((1S,2R)-2- hydroxycyclopentyl)-3- methoxybenzamide
265
Figure US09623028-20170418-C00280
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-((1S,2S)-2- hydroxycyclopentyl)-3- methoxybenzamide
266
Figure US09623028-20170418-C00281
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-((1R,2R)-2- hydroxycyclopentyl)-3- methoxybenzamide
267
Figure US09623028-20170418-C00282
 		(S)-4-(4-(cyclopentyloxy)-5-(2- methoxybenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- (tetrahydrofuran-3-yl)benzamide
268
Figure US09623028-20170418-C00283
 		N-(2-amino-2-oxoethyl)-4-(4- (cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
269
Figure US09623028-20170418-C00284
 		3-methoxy-N-methyl-4-(5- (pyridazin-4-yl)-4-(tetrahydro- 2H-pyran-4-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
270
Figure US09623028-20170418-C00285
 		3-methoxy-N-methyl-4-(5- (pyrimidin-4-yl)-4-(tetrahydro- 2H-pyran-4-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
271
Figure US09623028-20170418-C00286
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-methyl- N-((3-methyloxetan-3- yl)methyl)benzamide
272
Figure US09623028-20170418-C00287
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-methyl- N-(oxetan-3-yl)benzamide
273
Figure US09623028-20170418-C00288
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- (tetrahydro-2H-pyran-3- yl)benzamide
274
Figure US09623028-20170418-C00289
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- (tetrahydro-2H-pyran-3- yl)benzamide
275
Figure US09623028-20170418-C00290
 		(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxyphenyl)(4- methoxypiperidin-1- yl)methanone
276
Figure US09623028-20170418-C00291
 		(S)-4-(4-sec-butoxy-5-(1-methyl- 1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
277
Figure US09623028-20170418-C00292
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxybenzonitrile
278
Figure US09623028-20170418-C00293
 		4-(4-(cyclopentyloxy)-5-(1- methyl-1H-indazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
279
Figure US09623028-20170418-C00294
 		4-(4-(cyclopentyloxy)-5-(3- methylbenzo[d]isoxazol-6-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
280
Figure US09623028-20170418-C00295
 		5-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-4-methoxy-N- methylpicolinamide
281
Figure US09623028-20170418-C00296
 		N-((1,4-dioxan-2-yl)methyl)-4- (4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxybenzamide
282
Figure US09623028-20170418-C00297
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-ylmethyl)benzamide
283
Figure US09623028-20170418-C00298
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(3-hydroxypropyl)-3- methoxy-N-methylbenzamide
284
Figure US09623028-20170418-C00299
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(2- methoxyethyl)-N- methylbenzamide
285
Figure US09623028-20170418-C00300
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(2-hydroxy-2- methylpropyl)-3- methoxybenzamide
286
Figure US09623028-20170418-C00301
 		(S)-4-(4-sec-butoxy-5-(1-methyl- 1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N-(2- hydroxyethyl)-3- methoxybenzamide
287
Figure US09623028-20170418-C00302
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3- methoxybenzimidamide
288
Figure US09623028-20170418-C00303
 		4-(2-(2-methoxy-4- (methylcarbamoyl)phenylamino)- 4-(tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-5- yl)-N-methylpicolinamide
289
Figure US09623028-20170418-C00304
 		(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxyphenyl)(4,4- difluoropiperidin-1-yl)methanone
290
Figure US09623028-20170418-C00305
 		4-(5-(4-acetamido-3- hydroxyphenyl)-4- (cyclopentyloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
291
Figure US09623028-20170418-C00306
 		(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3- methoxyphenyl)((3R,4R)-3- hydroxy-4-methoxypyrrolidin-1- yl)methanone
292
Figure US09623028-20170418-C00307
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- (piperidin-1-yl)benzamide
293
Figure US09623028-20170418-C00308
 		4-(4-(cyclopentyloxy)-5-(2- ethoxybenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
294
Figure US09623028-20170418-C00309
 		4-(5-(4-amino-3-hydroxyphenyl)- 4-(cyclopentyloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
295
Figure US09623028-20170418-C00310
 		4-(cyclopentyloxy)-N-(1-methyl- 1H-pyrazol-5-yl)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine
296
Figure US09623028-20170418-C00311
 		4-(cyclopentyloxy)-N-(1,5- dimethyl-1H-pyrazol-4-yl)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine
297
Figure US09623028-20170418-C00312
 		4-(cyclopentyloxy)-N-(1,4- dimethyl-1H-pyrazol-3-yl)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine
298
Figure US09623028-20170418-C00313
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N,5- dimethylbenzamide
299
Figure US09623028-20170418-C00314
 		4-(4-(cyclopentyloxy)-5-(2-oxo- 2,3-dihydrobenzo[d]oxazol-6-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
300
Figure US09623028-20170418-C00315
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(1- methylazetidin-3-yl)benzamide
301
Figure US09623028-20170418-C00316
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(3- methyloxetan-3-yl)benzamide
302
Figure US09623028-20170418-C00317
 		4-(4-cyclobutoxy-5-(1-methyl- 1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-(oxetan-3- yl)benzamide
303
Figure US09623028-20170418-C00318
 		4-(4-(cyclopentyloxy)-5-(1- methyl-1H-yrazol-4-yl)7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
304
Figure US09623028-20170418-C00319
 		4-(4-cyclobutoxy-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
305
Figure US09623028-20170418-C00320
 		4-(4-(cyclopentyloxy)-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
306
Figure US09623028-20170418-C00321
 		4-(4-(cyclopentyloxy)-5- (quinolin-6-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
307
Figure US09623028-20170418-C00322
 		4-(cyclopentyloxy)-N-(1,3- dimethyl-1H-pyrazol-4-yl)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine
308
Figure US09623028-20170418-C00323
 		N-(1-acetylazetidin-3-yl)-4-(4- (cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxybenzamide
309
Figure US09623028-20170418-C00324
 		4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(2,2-difluoropropyl)- 3-methoxybenzamide
310
Figure US09623028-20170418-C00325
 		3-methoxy-4-(5-(4- (methylcarbamoyl)phenyl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(oxetan-3- yl)benzamide
311
Figure US09623028-20170418-C00326
 		(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3- methoxyphenyl)((3R,4R)-3,4- dimethoxypyrrolidin-1- yl)methanone
312
Figure US09623028-20170418-C00327
 		(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxyphenyl)(2,2- dimethylaziridin-1-yl)methanone
313
Figure US09623028-20170418-C00328
 		(S)-(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxyphenyl)(2- methylaziridin-1-yl)methanone
314
Figure US09623028-20170418-C00329
 		4-(4-((1s,4s)-4-hydroxy-4- methylcyclohexyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
315
Figure US09623028-20170418-C00330
 		aziridin-1-yl(4-(4-((1s,4s)-4- hydroxy-4- methylcyclohexyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3- methoxyphenyl)methanone
316
Figure US09623028-20170418-C00331
 		4-(4-(cyclopentyloxy)-2-(1- methyl-1H-pyrazol-5-ylamino)- 7H-pyrrolo[2,3-d]pyrimidin-5- yl)-N-methylbenzamide
317
Figure US09623028-20170418-C00332
 		N-methyl-4-(2-(1-methyl-1H- pyrazol-5-ylamino)-4-(tetrahydro- 2H-pyran-4-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-5- yl)benzamide
318
Figure US09623028-20170418-C00333
 		methyl 4-(4-(cyclopentyloxy)-2- (2-methoxy-4- (methylcarbamoyl)phenylamino)- 7H-pyrrolo[2,3-d]pyrimidin-5- yl)benzoate
319
Figure US09623028-20170418-C00334
 		4-(4-(cyclopentyloxy)-5-(4- fluoro-2-methylphenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
320
Figure US09623028-20170418-C00335
 		4-(4-(cyclopentyloxy)-5-(2,4- dimethoxyphenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
321
Figure US09623028-20170418-C00336
 		4-(4-(cyclopentyloxy)-5-(3,5- dimethylisoxazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
322
Figure US09623028-20170418-C00337
 		4-(4-(cyclopentyloxy)-5-(3- (dimethylamino)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N- methylbenzamide
323
Figure US09623028-20170418-C00338
 		4-(4-(cyclopentyloxy)-5-(3- hydroxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
324
Figure US09623028-20170418-C00339
 		4-(5-(3-cyanophenyl)-4- (cyclopentyloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
325
Figure US09623028-20170418-C00340
 		3-methoxy-4-(5-(5- methoxypyridin-3-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
326
Figure US09623028-20170418-C00341
 		3-methoxy-4-(4-(2- methoxyethoxy)-5-(1-methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N- methylbenzamide
327
Figure US09623028-20170418-C00342
 		N-(2-hydroxyethyl)-3-methoxy-4- (5-(1-methyl-1H-pyrazol-4-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
328
Figure US09623028-20170418-C00343
 		(S)-3-methoxy-N-methyl-4-(5-(1- methyl-1H-pyrazol-4-yl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
329
Figure US09623028-20170418-C00344
 		N-methyl-4-(2-(1-methyl-1H- pyrazol-5-ylamino)-4-(tetrahydro- 2H-pyran-4-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-5- yl)benzamide
330
Figure US09623028-20170418-C00345
 		4-(4-(cyclopentyloxy)-5-(4- fluoro-2-methylbenzo[d]oxazol- 6-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methylbenzamide
331
Figure US09623028-20170418-C00346
 		4-(4-cyclobutoxy-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(2-hydroxyethyl)-3- methoxybenzamide
332
Figure US09623028-20170418-C00347
 		4-(4-cyclobutoxy-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methyl-N-(oxetan-3- yl)benzamide
333
Figure US09623028-20170418-C00348
 		3-chloro-4-(4-cyclobutoxy-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(oxetan-3- yl)benzamide
334
Figure US09623028-20170418-C00349
 		4-(4-isopropoxy-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
335
Figure US09623028-20170418-C00350
 		(R)-(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxyphenyl)(2- methylaziridin-1-yl)methanone
336
Figure US09623028-20170418-C00351
 		4-(2-(4-(aziridine-1-carbonyl)-2- methoxyphenylamino)-4-((1s,4s)- 4-hydroxy-4- methylcyclohexyloxy)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-N- methylbenzamide
337
Figure US09623028-20170418-C00352
 		4-(4-((1s,4s)-4-hydroxy-4- methylcyclohexyloxy)-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
338
Figure US09623028-20170418-C00353
 		aziridin-1-yl(3-methoxy-4-(4- methoxy-5-(pyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)phenyl)methanone
339
Figure US09623028-20170418-C00354
 		4-(4-cyclobutoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
340
Figure US09623028-20170418-C00355
 		4-(4-cyclobutoxy-2-(1,3- dimethyl-1H-pyrazol-4-ylamino)- 7H-pyrrolo[2,3-d]pyrimidin-5- yl)-N-methylbenzamide
341
Figure US09623028-20170418-C00356
 		4-(4-(3-cyanocyclobutoxy)-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyimdin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
342
Figure US09623028-20170418-C00357
 		4-(2-(5-chloro-1-methyl-1H- pyrazol-4-ylamino)-4- cyclobutoxy-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-N- methylbenzamide
343
Figure US09623028-20170418-C00358
 		(S)-3-methoxy-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(oxetan-3- yl)benzamide
344
Figure US09623028-20170418-C00359
 		4-(4-cyclopropoxy-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
345
Figure US09623028-20170418-C00360
 		4-(4-(3,3-difluorocyclobutoxy)-5- (4-(methylcarbamoyl)phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
346
Figure US09623028-20170418-C00361
 		(R)-(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxyphenyl)(2- (hydroxymethyl)aziridin-1- yl)methanone
347
Figure US09623028-20170418-C00362
 		3-methoxy-4-(4-methoxy-5- (pyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N- (oxetan-3-yl)benzamide
348
Figure US09623028-20170418-C00363
 		4-(4-cyclobutoxy-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(1- methylazetidin-3-yl)benzamide
349
Figure US09623028-20170418-C00364
 		4-(4-((1s,4s)-4-hydroxy-4- methylcyclohexyloxy)-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(1- methylazetidin-3-yl)benzamide
350
Figure US09623028-20170418-C00365
 		(S)-(4-(4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxyphenyl)(2- (hydroxymethyl)aziridin-1- yl)methanone
351
Figure US09623028-20170418-C00366
 		N-(5-chloro-1-isopropyl-1H- pyrazol-4-yl)-4-(cyclopentyloxy)- 5-(2-methylbenzo[d]oxazol-6-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- amine
352
Figure US09623028-20170418-C00367
 		5-(4-cyclobutoxy-2-(2-methoxy- 4-(oxetan-3- ylcarbamoyl)phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-N- methylpicolinamide
353
Figure US09623028-20170418-C00368
 		4-(4-cyclobutoxy-2-(2-methoxy- 4-(oxetan-3- ylcarbamoyl)phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-2- fluoro-N-methylbenzamide
354
Figure US09623028-20170418-C00369
 		4-(4-tert-butoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(1- methylazetidin-3-yl)benzamide
355
Figure US09623028-20170418-C00370
 		4-(4-tert-butoxy-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(1- methylazetidin-3-yl)benzamide
356
Figure US09623028-20170418-C00371
 		4-(4-isopropoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(1- methylazetidin-3-yl)benzamide
357
Figure US09623028-20170418-C00372
 		4-(4-isopropoxy-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(1- methylazetidin-3-yl)benzamide
358
Figure US09623028-20170418-C00373
 		4-(4-((1s,4s)-4-hydroxy-4- methylcyclohexyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(1- methylazetidin-3-yl)benzamide
359
Figure US09623028-20170418-C00374
 		3-methoxy-4-(5-(4- (methylcarbamoyl)phenyl)-4- (oxetan-3-yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N- (oxetan-3-yl)benzamide
360
Figure US09623028-20170418-C00375
 		4-(5-(4-(1H-imidazol-2- yl)phenyl)-4-cyclobutoxy-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
361
Figure US09623028-20170418-C00376
 		4-(5-(4-(1H-imidazol-2- yl)phenyl)-4-(cyclopentyloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(1- methylazetidin-3-yl)benzamide
362
Figure US09623028-20170418-C00377
 		4-(4-isopropoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
363
Figure US09623028-20170418-C00378
 		4-(4-cyclopropoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(1- methylazetidin-3-yl)benzamide
364
Figure US09623028-20170418-C00379
 		4-(4-cyclopropoxy-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(1- methylazetidin-3-yl)benzamide
365
Figure US09623028-20170418-C00380
 		3-methoxy-4-(4-(2- methoxyethoxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(oxetan-3- yl)benzamide
366
Figure US09623028-20170418-C00381
 		3-methoxy-N-(1-methylazetidin- 3-yl)-4-(5-(4- (methylcarbamoyl)phenyl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
367
Figure US09623028-20170418-C00382
 		3-methoxy-N-(1-methylazetidin- 3-yl)-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
368
Figure US09623028-20170418-C00383
 		3-methoxy-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(oxetan-3- yl)benzamide
369
Figure US09623028-20170418-C00384
 		4-(4-cyclopropoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
370
Figure US09623028-20170418-C00385
 		4-(4-tert-butoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
371
Figure US09623028-20170418-C00386
 		1-(5-chloro-4-(4- (cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-1H-pyrazol-1-yl)-2- methylpropan-2-ol
372
Figure US09623028-20170418-C00387
 		4-(2-(5-chloro-1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4- ylamino)-4-cyclobutoxy-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-N- methylbenzamide
373
Figure US09623028-20170418-C00388
 		3-methoxy-4-(4-(2- methoxyethoxy)-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(oxetan-3- yl)benzamide
374
Figure US09623028-20170418-C00389
 		(S)-3-methoxy-N-(1- methylazetidin-3-yl)-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
375
Figure US09623028-20170418-C00390
 		(S)-3-methoxy-N-(1- methylazetidin-3-yl)-4-(5-(4- (methylcarbamoyl)phenyl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
376
Figure US09623028-20170418-C00391
 		(S)-3-methoxy-4-(5-(4- (methylcarbamoyl)phenyl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(oxetan-3- yl)benzamide
377
Figure US09623028-20170418-C00392
 		N-(5-chloro-1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4-yl)-4- (cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine
378
Figure US09623028-20170418-C00393
 		N-(5-chloro-1-(2-methoxyethyl)- 1H-pyrazol-4-yl)-4- (cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine
379
Figure US09623028-20170418-C00394
 		3-methoxy-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4-(1- methylcyclobutoxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(oxetan-3- yl)benzamide
380
Figure US09623028-20170418-C00395
 		3-methoxy-4-(4-methoxy-5-(3- methylbenzo[d]isoxazol-6-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(oxetan-3- yl)benzamide
381
Figure US09623028-20170418-C00396
 		4-(5-(2-fluoropyridin-4-yl)-4- methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-(oxetan-3- yl)benzamide
382
Figure US09623028-20170418-C00397
 		3-methoxy-4-(4-methoxy-5-(1- methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(oxetan-3- yl)benzamide
383
Figure US09623028-20170418-C00398
 		3-methoxy-4-(4-methoxy-5-(2- methylpyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(oxetan-3- yl)benzamide
384
Figure US09623028-20170418-C00399
 		4-(5-(2,6-dimethylpyridin-4-yl)- 4-methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-(oxetan-3- yl)benzamide
385
Figure US09623028-20170418-C00400
 		N-(5-chloro-1-ethyl-1H-pyrazol- 4-yl)-4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine
386
Figure US09623028-20170418-C00401
 		3-methoxy-4-(4-(2- methoxyethoxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(1-methylazetidin-3- yl)benzamide
387
Figure US09623028-20170418-C00402
 		4-(5-(1,3-dimethyl-1H-pyrazol-4- yl)-4-methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-(oxetan-3- yl)benzamide
388
Figure US09623028-20170418-C00403
 		3-methoxy-4-(4-methoxy-5-(3- methylbenzo[d]isoxazol-6-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
389
Figure US09623028-20170418-C00404
 		3-methoxy-4-(4-methoxy-5-(2- methoxypyridin-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-(oxetan-3- yl)benzamide
390
Figure US09623028-20170418-C00405
 		4-(5-(4-fluorophenyl)-4-methoxy- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N,3- trimethylbenzamide
391
Figure US09623028-20170418-C00406
 		4-(4-methoxy-5-(4- methoxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N,N,3- trimethylbenzamide
392
Figure US09623028-20170418-C00407
 		3-methoxy-4-(4-methoxy-5- (pyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N,N- dimethylbenzamide
393
Figure US09623028-20170418-C00408
 		N-(1,3-dimethyl-1H-pyrazol-4- yl)-4-methoxy-5-(pyridin-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- amine
394
Figure US09623028-20170418-C00409
 		4-(5-(2-chloropyridin-4-yl)-4- methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-(oxetan-3- yl)benzamide
395
Figure US09623028-20170418-C00410
 		3-methoxy-4-(4-methoxy-5- (pyrimidin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N- (oxetan-3-yl)benzamide
396
Figure US09623028-20170418-C00411
 		4-(4-methoxy-5-(pyridin-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methyl-N-(oxetan-3- yl)benzamide
397
Figure US09623028-20170418-C00412
 		4-(5-(4-(1H-imidazol-2- yl)phenyl)-4-methoxy-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N,3- trimethylbenzamide
398
Figure US09623028-20170418-C00413
 		4-(4-methoxy-5-(1-methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N,N,3- trimethylbenzamide
399
Figure US09623028-20170418-C00414
 		4-(4-methoxy-5-(2-methyl-1H- benzo[d]imidazol-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N,3- trimethylbenzamide
400
Figure US09623028-20170418-C00415
 		4-(4-methoxy-5-(3- methylbenzo[d]isoxazol-6-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N,3- trimethylbenzamide
401
Figure US09623028-20170418-C00416
 		4-methoxy-N-(1-methyl-1H- pyrazol-5-yl)-5-(pyridin-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- amine
402
Figure US09623028-20170418-C00417
 		4-(5-(2-fluoropyridin-4-yl)-4- isopropoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N,N,3- trimethylbenzamide
403
Figure US09623028-20170418-C00418
 		4-(5-(2-fluoropyridin-4-yl)-4- isopropoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N,N- dimethylbenzamide
404
Figure US09623028-20170418-C00419
 		3-methoxy-4-(4-methoxy-5-(2- methyl-1H-benzo[d]imidazol-5- yl)-7H-pyrrolo[2,3-d]pyrimidin- 2-ylamino)-N-(oxetan-3- yl)benzamide
405
Figure US09623028-20170418-C00420
 		3-methoxy-4-(4-methoxy-5- (pyridazin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N- (oxetan-3-yl)benzamide
406
Figure US09623028-20170418-C00421
 		4-(4-methoxy-5-(pyridin-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,3-dimethyl-N- (oxetan-3-yl)benzamide
407
Figure US09623028-20170418-C00422
 		4-(5-(1,2-dimethyl-1H- benzo[d]imidazol-6-yl)-4- methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N,N,3- trimethylbenzamide
408
Figure US09623028-20170418-C00423
 		3-methoxy-4-(4-methoxy-5-(3- methylbenzo[d]isoxazol-6-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N- dimethylbenzamide
409
Figure US09623028-20170418-C00424
 		4-(5-(2-fluoropyridin-4-yl)-4- methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N,N,3- trimethylbenzamide
410
Figure US09623028-20170418-C00425
 		4-(5-(1,2-dimethyl-1H- benzo[d]imidazol-5-yl)-4- methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N,N,3- trimethylbenzamide
411
Figure US09623028-20170418-C00426
 		4-(4-methoxy-5-(4- (methylsulfonyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N,N,3- trimethylbenzamide
412
Figure US09623028-20170418-C00427
 		4-(5-(2-fluoropyridin-4-yl)-4- methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N,N- dimethylbenzamide
413
Figure US09623028-20170418-C00428
 		4-(5-(2-fluoropyridin-4-yl)-4- methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-methyl-N-(oxetan-3- yl)benzamide
414
Figure US09623028-20170418-C00429
 		4-methoxy-N-(4-methyl-1H- indazol-5-yl)-5-(pyridin-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- amine
415
Figure US09623028-20170418-C00430
 		5-(5-(2-fluoropyridin-4-yl)-4- methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-4- methoxy-N,N- dimethylpicolinamide
416
Figure US09623028-20170418-C00431
 		5-(2-fluoropyridin-4-yl)-4- methoxy-N-(4-methoxy-6- (tetrahydro-2H-pyran-4- yl)pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine
417
Figure US09623028-20170418-C00432
 		4-(5-(3-chloro-1-methyl-1H- pyrazol-4-yl)-4-methoxy-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-methoxy-N-(oxetan- 3-yl)benzamide
418
Figure US09623028-20170418-C00433
 		4-(5-(2-fluoro-6-methylpyridin-4- yl)-4-methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N,N- dimethylbenzamide
419
Figure US09623028-20170418-C00434
 		N-(1,4-dimethyl-1H-indazol-5- yl)-4-methoxy-5-(pyridin-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- amine
420
Figure US09623028-20170418-C00435
 		4-(5-(2-fluoro-6-methylpyridin-4- yl)-4-methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-N,N,3- trimethylbenzamide
421
Figure US09623028-20170418-C00436
 		3-chloro-N-methyl-4-(5-(4- (methylcarbamoyl)phenyl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
422
Figure US09623028-20170418-C00437
 		3-chloro-4-(4-(cyclopentyloxy)-5- (2-methylbenzo[d]oxazol-6-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
423
Figure US09623028-20170418-C00438
 		3-chloro-N-methyl-4-(5-(1- methyl-1H-pyrazol-4-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
424
Figure US09623028-20170418-C00439
 		4-(5-(2-fluoro-6-methylpyridin-4- yl)-4-methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-(oxetan-3- yl)benzamide
425
Figure US09623028-20170418-C00440
 		3-chloro-4-(4-(cyclopentyloxy)-5- (4-(methylcarbamoyl)phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
426
Figure US09623028-20170418-C00441
 		3-chloro-4-(4-isopropoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
427
Figure US09623028-20170418-C00442
 		3-chloro-4-(4-methoxy-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
428
Figure US09623028-20170418-C00443
 		3-chloro-4-(4-methoxy-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
429
Figure US09623028-20170418-C00444
 		3-chloro-4-(4-((1s,4s)-4-hydroxy- 4-methylcyclohexyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
430
Figure US09623028-20170418-C00445
 		3-chloro-N-methyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-ylamino)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
431
Figure US09623028-20170418-C00446
 		3-chloro-N-(2-hydroxyethyl)-4- (5-(2-methylbenzo[d]oxazol-6- yl)-4-(tetrahydro-2H-pyran-4- yloxy)-7H-pyrrolo[2,3- d]pyrimidin-2- ylamino)benzamide
432
Figure US09623028-20170418-C00447
 		3-chloro-4-(4-isopropoxy-5-(4- (methylcarbamoyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)-N-methylbenzamide
433
Figure US09623028-20170418-C00448
 		3-chloro-N-methyl-4-(5-(4- (methylcarbamoyl)phenyl)-4- (tetrahydro-2H-pyran-4-ylamino)- 7H-pyrolo[2,3-d]pyrimidin-2- ylamino)benzamide
434
Figure US09623028-20170418-C00449
 		(R)-3-chloro-N-methyl-4-(5-(4- (methylcarbamoyl)phenyl)-4- (tetrahydrofuran-3-yloxy)-7H- pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
435
Figure US09623028-20170418-C00450
 		3-ethyl-N-methyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)benzamide
436
Figure US09623028-20170418-C00451
 		N-methyl-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrrolo[2,3-d]pyrimidin-2- ylamino)-3-propylbenzamide
437
Figure US09623028-20170418-C00452
 		4-(5-(2-chloro-6-methylpyridin-4- yl)-4-methoxy-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino)-3- methoxy-N-(oxetan-3- yl)benzamide
438
Figure US09623028-20170418-C00453
 		3-chloro-4-(5-(2- methylbenzo[d]oxazol-6-yl)-4- (tetrahydro-2H-pyran-4-yloxy)- 7H-pyrolo[2,3-d]pyrimidin-2- ylamino)-N-(oxetan-3- yl)benzamide
Methods for Making Pyrrolopyrimidine Compounds
The Pyrrolopyrimidine Compounds described herein can be obtained using conventional organic syntheses and commercially available starting materials.
Starting materials useful for preparing compounds of formula (I) and intermediates therefore, are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents.
Particular methods for preparing compounds of formula (I) are disclosed in U.S. patent application Ser. No. 14/155,485, filed Jan. 15, 2014, and U.S. patent application Ser. No. 14/155,498, filed Jan. 15, 2014, each incorporated by reference herein in their entirety.
Methods of Use
The Pyrrolopyrimidine Compounds have utility as pharmaceuticals to treat, prevent or improve cancer in animals or humans. Accordingly, the Pyrrolopyrimidine Compounds provided herein can be used in all the methods as provided herein. Particularly, the Pyrrolopyrimidine Compounds provided herein can be used in the treatment, prevention or improvement of all diseases disorders, or conditions provided herein. Accordingly, provided herein are uses of the Pyrrolopyrimidine Compounds, including the treatment or prevention of those cancers set forth below. The methods provided herein comprise the administration of an effective amount of one or more Pyrrolopyrimidine Compound(s) to a subject in need thereof.
In another aspect, provided herein are methods for treating or preventing a cancer, comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound, as described herein. In some embodiments, the cancer is a solid tumor or a hematological tumor. In some embodiments, the cancer is not triple negative breast cancer (TNBC).
In some embodiments, the solid tumor is bladder cancer (including superficial bladder cancer), breast cancer (including luminal B type, ER+, PR+ and Her2+ breast cancer), central nervous system cancer (including glioblastoma multiforme (GBM), glioma, medulloblastoma, and astrocytoma), colorectal cancer, gastrointestinal cancer (including stomach cancer, oesophagus cancer, and rectum cancer), endocrine cancer (including thyroid cancer, and adrenal gland cancer), eye cancer (including retinoblastoma), female genitourinary cancer (including cancer of the placenta, uterus, vulva, ovary, cervix), head and neck cancer (including cancer of the pharynx, oesophagus, and tongue), liver cancer, lung cancer (including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), mucoepidermoid, bronchogenic, squamous cell carcinoma (SQCC), and analplastic/NSCLC), skin cancer (including melanoma, and SQCC), soft tissue cancer (including sarcoma, Ewing's sarcoma, and rhabdomyosarcoma), bone cancer (including sarcoma, Ewing's sarcoma, and osteosarcoma), squamous cell cancer (including lung, esophageal, cervical, and head and neck cancer), pancreas cancer, kidney cancer (including renal Wilm's tumor and renal cell carcinoma), or prostate cancer. In some embodiments, the solid tumor is breast cancer, colon cancer, lung cancer or bladder cancer. In one such embodiment, the solid tumor is superficial bladder cancer. In another, the solid tumor is lung squamous cell carcinoma. In yet another embodiment, the solid tumor is luminal B type breast cancer.
In some embodiments, the hematological cancer is leukemia (including acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), acute T-cell leukemia, B cell precursor leukemia, acute promyelocytic leukemia (APML), plasma cell leukemia, myelomonoblastic/T-ALL, B myelomonocytic leukemia, erythroleukemia, and acute myeloid leukemia (AML)), lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), B cell lymphoma, lymphoblastic lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and large cell immunoblastic lymphoma), or multiple myeloma.
In some embodiments, provided herein are methods for preventing cancer metastasis, comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound, as described herein. In some embodiments, the cancer is a metastatic cancer, in particular, a metastatic solid tumor or metastatic hematologic cancer, wherein the solid tumor and hematologic cancer is as described herein. In other embodiments, provided herein are methods of preventing cancer metastasis, comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound, as described herein. In yet another aspect, provided herein are methods of eradicating cancer stem cells in a subject, comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound, as described herein. In other embodiments, provided herein are methods of inducing differentiation in cancer stem cells in a subject, comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound, as described herein. In other embodiments, provided herein are methods of inducing cancer stem cell death in a subject, comprising administering to a subject in need thereof an effective amount of a Pyrrolopyrimidine Compound, as described herein. In some such embodiments, the cancer is a solid tumor, for example a CNS cancer (e.g. GBM) or breast cancer, or a hematological cancer, such as leukemia.
In another aspect, provided herein are methods for treating or preventing a cancer, in particular a solid tumor or a hematological tumor as described herein, comprising administering to a subject in need thereof an effective amount of a compound that inhibits TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity. In some embodiments, provided are methods for treating or preventing a cancer, in particular a solid tumor or a hematological tumor as described herein, comprising administering to a subject in need thereof an effective amount of a compound that inhibits TTK, CLK1, and CLK2 kinase activity. In some embodiments, the TTK, CLK1, and CLK2 kinase activity is inhibited in a cell. In some embodiments, the TTK, CLK1, and CLK2 kinase activity is inhibited in vivo. In some embodiments, the compound that inhibits TTK, CLK1, and CLK2 kinase activity is a Pyrrolopyrimidine Compound as described herein. In another aspect, provided herein are methods for treating or preventing a cancer associated with the pathways involving TTK, CLK1, and CLK2, and optionally CAMKK2, and mutants or isoforms thereof, comprising administering to a subject in need thereof an effective amount of a compound that inhibits TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity. In some embodiments, the cancer associated with the TTK, CLK1, and CLK2, and optionally CAMKK2, pathways include a solid tumor or a hematological tumor as described herein. In some embodiments, the TTK, CLK1, and CLK2, and optionally CAMKK2, pathway is inhibited in a cell. In some embodiments, the TTK, CLK1, and CLK2, and optionally CAMKK2, pathway is inhibited in vivo. In some embodiments, the compound that inhibits TTK, CLK1, and CLK2, and optionally CAMKK2, pathway is a Pyrrolopyrimidine Compound as described herein.
In certain embodiments, provided herein are methods for measuring inhibition of TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity, in a patient having a cancer, for example a solid tumor or a hematological tumor as described herein, comprising administering an effective amount of a Pyrrolopyrimidine Compound to said patient, measuring the amount of TTK, CLK1, and CLK2 kinase activity in said patient, and comparing said amount of TTK, CLK1, and CLK2 kinase activity to that of said patient prior to administration of an effective amount of a Pyrrolopyrimidine Compound. In certain embodiments, less TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity, in said biological sample obtained after administration of said Pyrrolopyrimidine Compound relative to the amount of TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity, in said biological sample obtained prior to administration of said Pyrrolopyrimidine Compound indicates inhibition.
In one embodiment, the kinase activity is measured using a radioactivity based kinase assay, which measures the incorporation of a radioactively labeled phosphate moiety (for example, 33P labeled phosphate) into a substrate, for example, a peptide substrate. Reduced levels of radioactively labeled phosphate incorporation into the substrate indicates inhibition of kinase activity. In another embodiment, the kinase activity is measured using a time-resolved-fluorescence resonance energy transfer (TR-FRET) based kinase assay, which measures loss of fluorescence as a result of substrate phosphorylation, for example, a peptide substrate (see for example Invitrogen Z'-Lyte Assay®). Increased levels of fluorescence indicates inhibition of kinase activity. In another embodiment, the kinase activity is measured using a competitive tracer binding assay (for example, Invitrogen Lanthascreen® Eu binding assay), which measures fluorescence as a result of tracer binding (for example ATP site binding). Reduced fluorescence indicates displacement of tracer binding, which indicates inhibition of kinase activity. In yet another embodiment, the kinase activity is measured using a cellular biomarker assay, which measures the phosphorylation of a substrate, for example a downstream substrate, using Western Blot, ELISA or Mesoscale. Reduced phosphorylation of the substrate indicates inhibition of kinase activity.
In some embodiments, the inhibition of TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity, is assessed in a biological sample of the patient, such as in circulating blood cells, or tumor or skin biopsies. In such embodiments, the amount of inhibition of kinase activity is assessed by comparison of the amount of phosphorylated substrate (for example for TTK: phospho-TTK, such as p-TTK T686, or phosphorylated borealin, BubR1, Chk2, c-Abl, p53, Mip1 or TACC2; and for CLK2 (phospho-SRp75, or phosphorylated PP2A regulatory subunit B56β (PPP2R5B, B′β) or PGC-1α) before and after administration of the Pyrrolopyrimidine Compound to the patient. In some such embodiments, less phosphorylated TTK substrate and less phosphorylated CLK2 substrate, in said biological sample, obtained after administration of said Pyrrolopyrimidine Compound relative to the amount of phosphorylated TTK substrate and phosphorylated CLK2 substrate, in said biological sample obtained prior to administration of said Pyrrolopyrimidine Compound indicates inhibition. In some such embodiments, less phospho-TTK (for example p-TTK T686) and phospho-SRp75, in said biological sample obtained after administration of said Pyrrolopyrimidine Compound relative to the amount of phospho-TTK (for example p-TTK T686) and phospho-SRp75, in said biological sample obtained prior to administration of said Pyrrolopyrimidine Compound indicates inhibition.
In certain embodiments, provided herein are methods for inhibiting TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity, in a patient having a cancer, in particular a solid tumor or a hematological tumor as described herein, comprising administering an effective amount of a Pyrrolopyrimidine Compound to said patient. In some embodiments, the methods additionally comprise comparing the amount of TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 activity, in a biological sample of a patient obtained prior to and after administration of said Pyrrolopyrimidine Compound, wherein less TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity, in said biological sample obtained after administration of said Pyrrolopyrimidine Compound relative to the amount of TTK, CLK1, and CLK2 kinase activity, and optionally CAMKK2 kinase activity, in said biological sample obtained prior to administration of said Pyrrolopyrimidine Compound indicates inhibition.
In some embodiments, the methods additionally comprise comparing the amount of phosphorylated substrate (for example for TTK: phospho-TTK, such as p-TTK T686, or phosphorylated borealin, BubR1, Chk2, c-Abl, p53, Mip1 or TACC2; and for CLK2 (phospho-SRp75, or phosphorylated PP2A regulatory subunit B56β (PPP2R5B, B′β) or PGC-1α) in a biological sample of a patient obtained prior to and after administration of said Pyrrolopyrimidine Compound, wherein less phosphorylated substrate in said biological sample obtained after administration of said Pyrrolopyrimidine Compound relative to the amount of phosphorylated substrate in said biological sample obtained prior to administration of said Pyrrolopyrimidine Compound indicates inhibition. In other embodiments, the methods additionally comprise comparing the amount of phospho-TTK (for example p-TTK T686) and phospho-SRp75, in a biological sample of a patient obtained prior to and after administration of said Pyrrolopyrimidine Compound, wherein less phospho-TTK (for example p-TTK T686) and phospho-SRp75, in said biological sample obtained after administration of said Pyrrolopyrimidine Compound relative to the amount of phospho-TTK (for example p-TTK T686) and phospho-SRp75, in said biological sample obtained prior to administration of said Pyrrolopyrimidine Compound indicates inhibition.
In some embodiments, the TTK kinase activity is inhibited with an IC50 no greater than about 20 nM. In another, the TTK kinase activity is inhibited with an IC50 between about 0.01 nM and about 20 nM. In others, the TTK kinase activity is inhibited with an IC50 between about 0.01 nM and about 100 nM. In still others, the TTK kinase activity is inhibited with an IC50 between about 0.01 nM and about 200 nM. In yet others, the TTK kinase activity is inhibited with an IC50 between about 0.1 nM and about 500 nM. In some embodiments, the CLK1 kinase activity is inhibited with an IC50 no greater than about 300 nM. In some embodiments, the CLK1 kinase activity is inhibited with an IC50 between about 1 nM and about 100 nM. In others, the CLK1 kinase activity is inhibited with an IC50 between about 1 nM and about 500 nM. In yet others, the CLK1 kinase activity is inhibited with an IC50 between about 1 nM and about 1000 nM. In some embodiments, the CLK2 kinase activity is inhibited with an IC50 no greater than about 10 nM. In another, the CLK2 kinase activity is inhibited with an IC50 between about 0.01 nM and about 20 nM. In others, the CLK2 kinase activity is inhibited with an IC50 between about 0.01 nM and about 100 nM. In still others, the CLK2 kinase activity is inhibited with an IC50 between about 0.01 nM and about 200 nM. In yet others, the CLK2 kinase activity is inhibited with an IC50 between about 0.1 nM and about 500 nM. In some embodiments, the CAMKK2 kinase activity is inhibited with an IC50 no greater than about 1000 nM. In another, the CAMKK2 kinase activity is inhibited with an IC50 between about 1 nM and about 500 nM. In others, the CAMKK2 kinase activity is inhibited with an IC50 between about 1 nM and about 1000 nM. In still others, the CAMKK2 kinase activity is inhibited with an IC50 between about 1 nM and about 2000 nM. In yet others, the CAMKK2 kinase activity is inhibited with an IC50 between about 1 nM and about 5000 nM.
In one embodiment, provided herein are methods for achieving a Response Evaluation Criteria in Solid Tumors (RECIST 1.1) of complete response, partial response or stable disease in a patient comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein. In another embodiment, provided herein are methods to increase Progression Free Survival rates, as determined by Kaplan-Meier estimates.
In one embodiment, provided herein are methods for preventing or delaying a Response Evaluation Criteria in Solid Tumors (RECIST 1.1) of progressive disease in a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a solid tumor as described herein. In one embodiment the prevention or delaying of progressive disease is characterized or achieved by a change in overall size of the target lesions, of for example, between −30% and +20% compared to pre-treatment. In another embodiment, the change in size of the target lesions is a reduction in overall size of more than 30%, for example, more than 50% reduction in target lesion size compared to pre-treatment. In another, the prevention is characterized or achieved by a reduction in size or a delay in progression of non-target lesions compared to pre-treatment. In one embodiment, the prevention is achieved or characterized by a reduction in the number of target lesions compared to pre-treatment. In another, the prevention is achieved or characterized by a reduction in the number or quality of non-target lesions compared to pre-treatment. In one embodiment, the prevention is achieved or characterized by the absence or the disappearance of target lesions compared to pre-treatment. In another, the prevention is achieved or characterized by the absence or the disappearance of non-target lesions compared to pre-treatment. In another embodiment, the prevention is achieved or characterized by the prevention of new lesions compared to pre-treatment. In yet another embodiment, the prevention is achieved or characterized by the prevention of clinical signs or symptoms of disease progression compared to pre-treatment, such as cancer-related cachexia or increased pain.
In certain embodiments, provided herein are methods for decreasing the size of target lesions in a patient compared to pre-treatment, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein.
In certain embodiments, provided herein are methods for decreasing the size of a non-target lesion in a patient compared to pre-treatment, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein.
In certain embodiments, provided herein are methods for achieving a reduction in the number of target lesions in a patient compared to pre-treatment, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein.
In certain embodiments, provided herein are methods for achieving a reduction in the number of non-target lesions in a patient compared to pre-treatment, comprising administering an effective amount a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein.
In certain embodiments, provided herein are methods for achieving an absence of all target lesions in a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein.
In certain embodiments, provided herein are methods for achieving an absence of all non-target lesions in a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein.
In certain embodiments, provided herein are methods for treating a cancer, in particular a solid tumor as described herein, the methods comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor, wherein the treatment results in a complete response, partial response or stable disease, as determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
In certain embodiments, provided herein are methods for treating a cancer, in particular a solid tumor as described herein, the methods comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein, wherein the treatment results in a reduction in target lesion size, a reduction in non-target lesion size and/or the absence of new target and/or non-target lesions, compared to pre-treatment.
In certain embodiments, provided herein are methods for treating a cancer, in particular a solid tumor as described herein, the methods comprising administering an effective amount a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor as described herein, wherein the treatment results in prevention or retarding of clinical progression, such as cancer-related cachexia or increased pain.
In another embodiment, provided herein are methods for inducing a therapeutic response characterized with the International Workshop Criteria (IWC) for NHL (see Cheson B D, Pfistner B, Juweid, M E, et. al. Revised Response Criteria for Malignant Lymphoma. J. Clin. Oncol: 2007: (25) 579-586) of a patient, comprising administering an effective amount a Pyrrolopyrimidine Compound to a patient having a cancer, in particular hematological cancers such as lymphoma, as described herein. In another embodiment, provided herein are methods for achieving complete remission, partial remission or stable disease, as determined by the International Workshop Criteria (IWC) for NHL in a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular hematological cancers such as lymphoma, as described herein. In another embodiment, provided herein are methods for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, disease-free survival or lymphoma-free survival as determined by the International Workshop Criteria (IWC) for NHL in a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular hematological cancers such as lymphoma, as described herein.
In another embodiment, provided herein are methods for inducing a therapeutic response assessed with the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie B G M, Harousseau J-L, Miguel J S, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006; (10) 10: 1-7) of a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular multiple myeloma. In another embodiment, provided herein are methods for achieving a stringent complete response, complete response, or very good partial response, as determined by the International Uniform Response Criteria for Multiple Myeloma (IURC) in a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular multiple myeloma. In another embodiment, provided herein are methods for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular multiple myeloma.
In another embodiment, provided herein are methods for inducing a therapeutic response assessed with the Response Assessment for Neuro-Oncology (RANO) Working Group for GBM (see Wen P., Macdonald, D R., Reardon, D A., et al. Updated response assessment criteria for highgrade gliomas: Response assessment in neuro-oncology working group. J. Clin. Oncol. 2010; 28: 1963-1972) of a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular glioblastoma multiforme (GBM). In one embodiment, RANO will be used to establish the proportion of subjects progression-free at 6 months from Day 1 relative to efficacy evaluable subjects in the GBM type.
In another embodiment, provided herein are methods for improving the Eastern Cooperative Oncology Group Performance Status (ECOG) of a patient, comprising administering an effective amount a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor or hematological cancer as described herein.
In another embodiment, provided herein are methods for inducing a therapeutic response assessed by Positron Emission Tomography (PET) outcome of a patient, comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor or hematological cancer as described herein. In certain embodiments, provided herein are methods for treating a cancer, in particular a solid tumor or hematological cancer as described herein, the methods comprising administering an effective amount of a Pyrrolopyrimidine Compound to a patient having a cancer, in particular a solid tumor or hematological cancer as described herein, wherein the treatment results in a reduction in tumor metabolic activity, for example, as measured by PET imaging.
In some embodiments of the methods described herein, the Pyrrolopyrimidine Compound is a compound as described herein. In one embodiment, the Pyrrolopyrimidine Compound is a compound of formula (I). In another embodiment, the Pyrrolopyrimidine Compound is a compound from Table A. In one embodiment, the Pyrrolopyrimidine Compound is a Pyrrolopyrimidine Compound set forth herein having molecular formula C26H24N6O4. In another, the Pyrrolopyrimidine Compound is a Pyrrolopyrimidine Compound set forth herein having molecular formula C26H26N6O4. In yet another, the Pyrrolopyrimidine Compound is a Pyrrolopyrimidine Compound set forth herein having molecular formula C26H27N5O4. In yet another, the Pyrrolopyrimidine Compound is a Pyrrolopyrimidine Compound set forth herein having molecular formula C28H28N6O4. In still another, the Pyrrolopyrimidine Compound is a Pyrrolopyrimidine Compound set forth herein having molecular formula C28H30N6O4. In another embodiment, the Pyrrolopyrimidine Compound is a Pyrrolopyrimidine Compound set forth herein having molecular formula C29H30N6O5. In one embodiment, the Pyrrolopyrimidine Compound is 4-((4-(cyclopentyloxy)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (Compound 3). In another, the Pyrrolopyrimidine Compound is 4-((4-cyclopropoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (Compound 152). In yet another, the Pyrolopyrimidine is 4-((4-isopropoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (Compound 125). In still another, the Pyrolopyrimidine is 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (Compound 38). In another embodiment, the Pyrolopyrimidine is 4-((4-(cyclopentyloxy)-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (Compound 79). In yet another embodiment, the Pyrolopyrimidine is 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-3-methoxybenzamide (Compound 101).
Further provided herein are methods for treating patients who have been previously treated for a cancer, in particular a solid tumor or a hematological cancer as described herein, as well as those who have not previously been treated. Because patients with a cancer have heterogenous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on his/her prognosis. The skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based standard therapy that can be effectively used to treat an individual patient with a cancer.
Pharmaceutical Compositions and Routes of Administration
The Pyrrolopyrimidine Compounds can be administered to a subject parenterally in the conventional form of preparations, such as injections, suspensions, solutions and emulsions. Suitable vehicles that can be used to provide intravenous formulations of a Pyrrolopyrimidine Compound are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. An intravenous formulation can be prepared by reconstituting a Pyrrolopyrimidine Compound with such a suitable liquid vehicle. A desired concentration of the intravenous formulation can be obtained by reconstituting an appropriate amount of a Pyrrolopyrimidine Compound with an appropriate volume of liquid vehicle. A desired concentration of the intravenous formulation provides a therapeutically effective amount of a Pyrrolopyrimidine Compound to the patient in need of the intravenous formulation and maintains a therapeutically effective level of a Pyrrolopyrimidine Compound in the patient. The dose which is therapeutically effective will depend on the rate at which the intravenous formulation is delivered to the patient and the concentration of the intravenous formulation.
The effective amount of the Pyrrolopyrimidine Compound in the pharmaceutical composition may be at a level that will exercise the desired effect; for example, about 0.005 mg/kg of a subject's body weight to about 100 mg/kg of a subject's body weight in unit dosage for parenteral administration.
The dose of a Pyrrolopyrimidine Compound to be administered to a subject is rather widely variable and can be subject to the judgment of a health-care practitioner. In general, the Pyrrolopyrimidine Compounds can be administered one to seven times a week, once every two weeks, once every three weeks or once every four weeks in a dose of about 0.005 mg/kg of a subject's body weight to about 10 mg/kg of a subject's body weight in a subject, but the above dosage may be properly varied depending on the age, body weight and medical condition of the subject and the type of administration. In one embodiment, the dose is about 0.01 mg/kg of a subject's body weight to about 5 mg/kg of a subject's body weight, about 0.05 mg/kg of a subject's body weight to about 1 mg/kg of a subject's body weight, about 0.1 mg/kg of a subject's body weight to about 0.75 mg/kg of a subject's body weight or about 0.25 mg/kg of a subject's body weight to about 0.5 mg/kg of a subject's body weight. In one embodiment, one dose is given per week. In others, one dose is given two, three or four times per week. In still others, one dose is given per two weeks, per three weeks or per four weeks. In any given case, the amount of the Pyrrolopyrimidine Compound administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.
In another embodiment, provided herein are methods for the treatment or prevention of a disease or disorder comprising the administration of about 0.375 mg/dose to about 750 mg/dose, about 0.75 mg/dose to about 375 mg/dose, about 3.75 mg/dose to about 75 mg/dose, about 7.5 mg/dose to about 55 mg/dose or about 18 mg/dose to about 37 mg/dose of a Pyrrolopyrimidine Compound to a subject in need thereof.
In another embodiment, provided herein are methods for the treatment or prevention of a disease or disorder comprising the administration of about 1 mg/dose to about 1200 mg/dose, about 10 mg/dose to about 1200 mg/dose, about 100 mg/dose to about 1200 mg/dose, about 400 mg/dose to about 1200 mg/dose, about 600 mg/dose to about 1200 mg/dose, about 400 mg/dose to about 800 mg/dose or about 600 mg/dose to about 800 mg/dose of a Pyrrolopyrimidine Compound to a subject in need thereof. In a particular embodiment, the methods disclosed herein comprise the administration of 400 mg/dose, 600 mg/dose or 800 mg/dose of a Pyrrolopyrimidine Compound to a subject in need thereof.
In another embodiment, provided herein are unit dosage formulations that comprise between about 1 mg and 200 mg, about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, or about 500 mg and about 1000 mg of a Pyrrolopyrimidine Compound.
In a particular embodiment, provided herein are unit dosage formulations comprising about 100 mg or 400 mg of a Pyrrolopyrimidine Compound.
In another embodiment, provided herein are unit dosage formulations that comprise 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a Pyrrolopyrimidine Compound.
A Pyrrolopyrimidine Compound can be administered once, twice, three, four or more times daily. In a particular embodiment, doses of 600 mg or less are administered as a once daily dose and doses of more than 600 mg are administered twice daily in an amount equal to one half of the total daily dose.
In another embodiment, provided herein are compositions comprising an effective amount of a Pyrrolopyrimidine Compound and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.
The compositions can be in the form of solutions, parenteral solutions, and suspensions and the like. Compositions can be formulated to contain a single dose, or a convenient fraction of a single dose, in a dosage unit, which may be a single vial or convenient volume of a liquid. In one embodiment, the solutions are prepared from water-soluble salts, such as the hydrochloride salt. In general, all of the compositions are prepared according to known methods in pharmaceutical chemistry.
The effect of the Pyrrolopyrimidine Compound can be delayed or prolonged by proper formulation. The parenteral preparations can be made long-acting, by dissolving or suspending the Pyrrolopyrimidine Compound in oily or emulsified vehicles that allow it to disperse slowly in the serum.
EXAMPLES
The following Examples are presented by way of illustration, not limitation.
ENZYME ASSAYS
CLK1 Kinase Assay.
A fluorescence resonance energy transfer-based Z'-LYTE® kinase assay kit-Ser/Thr 09 (Invitrogen, Carlsbad, Calif., cat.# PV3324) was used to determine the IC50 values for inhibition of CLK1 kinase activity. The reactions were performed in a 384-well plate with a 10 μl reaction volume per well containing CLK1 enzyme (16.2-128 ng), 25 μM adenosine triphosphate (ATP), 2 μM Z'-Lyte® Ser/Thr 9 peptide substrate in 50 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.5, 0.01% Brij-35, 10 mM magnesium chloride (MgCl2), 1 mM ethylene glycol tetraacetic acid (EGTA) buffer with a serial 3-fold dilution of the test compounds. After a 1 hour incubation, 5 μL of Development Reagent A (1:256 dilution) was added, and the fluorescence ratio was calculated. The dose-response curves were fitted to a sigmoidal dose-response model using XLfit from IDBS. The IC50 values were determined as the concentration of compound resulting in 50% of remaining enzyme activity. Results for certain Pyrrolopyrimidine Compounds are shown in Tables B and C.
CLK2 Kinase Assay.
A fluorescence resonance energy transfer-based Z'-LYTE® kinase assay kit-Ser/Thr 6 peptide (Invitrogen, Carlsbad, Calif., cat.# PV3179) was used to determine the IC50 values for inhibition of CLK2 kinase activity. The reactions were performed in a 384-well plate with a 10 μl reaction volume per well containing CLK2 enzyme (ranging from 0.97-11.5 ng), 25 μM ATP, 2 μM Z'-Lyte® Ser/Thr 6 peptide substrate in 50 mM HEPES, pH 7.5, 0.01% Brij-35, 10 mM MgCl2, 1 mM EGTA buffer with a serial 3-fold dilution of the test compounds. After a 1 hour incubation, 5 μL of Development Reagent A (1:2048 dilution) was added, and the fluorescence ratio was calculated. A dose-response curves were fitted to a sigmoidal dose-response model using XLfit from IDBS. The IC50 values were determined as the concentration of compound resulting in 50% of remaining enzyme activity. Results for certain Pyrrolopyrimidine Compounds are shown in Tables B and C.
TTK Kinase Assay.
The LanthaScreen® Eu Kinase Binding Assay (Invitrogen, Carlsbad, Calif. cat.#) was used to determine the IC50 values for inhibition of TTK kinase activity. The reaction was performed in a 384-well plate with a 16 μL reaction volume per well containing 5 nM TTK enzyme, 30 nM of Tracer 236 (Invitrogen PV5592), and 2 nM LanthaScreen® Eu-anti-GST antibody in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA buffer with a serial 3-fold dilution of test compound. The reaction was incubated for 1 hour at room temperature and then read on a fluoresence plate reader (Excitation 340 nm, Kinase Tracer 236 Emission: 665 nm, LanthaScreen™ Eu-anti-Tag Antibody: Emission 615 nm). The TR-FRET ratio was calculated as the intensity of the acceptor signal (665 nm) divided by the intensity of the donor signal (615 nm). The dose-response curves were fitted to a sigmoidal dose-response model using XLfit from IDBS. The IC50 values were determined as the concentration of compound resulting in 50% of displaced Tracer 236 (ATP competive inhibitor). Results for certain Pyrrolopyrimidine Compounds are shown in Tables B and C.
CAMKK2 Kinase Assay.
The LanthaScreen® Eu Kinase Binding Assay (Invitrogen, Carlsbad, Calif.) was used to determine the IC50 values for inhibition of CAMKK2 kinase activity. The reaction was performed in a 384-well plate with a 16 μL reaction volume per well containing 5 nM CAMKK2 enzyme, 10 nM of Kinase Tracer 236, and 2 nM LanthaScreen® Eu-anti-GST antibody in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA buffer with a serial 3-fold dilution of test compound. The reaction was incubated for 1 hour at room temperature and then read on a fluoresence plate reader (Excitation 340 nm, Kinase Tracer 236 Emission: 665 nm, and LanthaScreen™ Eu-anti-Tag Antibody: Emission 615 nm). The TR-FRET ratio was calculated as the intensity of the acceptor signal (665 nm) divided by the intensity of the donor signal (615 nm). The dose-response curves were fitted to a sigmoidal dose-response model using XLfit from IDBS. The IC50 values were determined as the concentration of compound resulting in 50% of displaced Tracer 236 (ATP competive inhibitor).
Alternative CAMKK2 Kinase Assay.
CAMKK2 enzyme was mixed with 1 μM of Ca2+-Calmodulin and 10 μM of the Mylein Basic Protein (MBP) substrate in reaction buffer; 20 mM 4-(2-hydroxyethyl)-1-piperazineethane sulfonic acid (HEPES), 10 mM magnesium chloride (MgCl2), 1 mM ethyleneglycoltetraacetic acid (EGTA), 0.02% Brij35, 0.02 mg/ml bovine serum albumin (BSA), 0.1 mM sodium orthovanadate, 2 mM dithiothreitol (DTT), 1% dimethyl sulfoxide (DMSO) at pH 7.5. Compounds were delivered into the reaction, followed 20 min later by addition of a mixture of ATP (Sigma) and 33P ATP (PerkinElmer) to a final concentration of 10 μM. Reactions were carried out at 25° C. for 120 min, followed by spotting of the reactions onto P81 ion exchange filter paper (Whatman). Unbound phosphate was removed by extensive washing of filters in 0.75% phosphoric acid. After subtraction of background derived from control reactions containing inactive enzyme, kinase activity data were expressed as the percent remaining kinase activity in test samples compared to the DMSO vehicle reactions. IC50 values and curve fits were obtained using Prism (GraphPad Software). Results for certain Pyrrolopyrimidine Compounds are shown in Tables C.
TABLE B
Inhibition by Pyrrolopyrimidine Compounds of TTK, CLK1, and CLK2
kinase activity (% inhibition at 3 μM.
Cmpd No. TTK (% Inh.) CLK1 (% Inh.) CLK2 (% Inh.)
3 91 104
11 95 94
16 92 90
17 97 98
38 99 98
58 96 103
64 68 99
79 97 97
89 101 100
90 101 101
98 103 104
101 95 98
118 102 98 98
132 92 98
133 104 101
134 101 100
139 104 99
140 97 103
145 96 97
146 103 100
148 99 106
150 99 111
152 99 100
157 95 105
160 98 108
162 100 106
163 100 102
169 100 105
171 97 102
184 101 98
185 98 106
191 100 99
192 102 101 103
193 100 99
197 100 103
198 93 100
201 100 103
202 99 99
203 98 99
204 98 99
205 99 103
206 92 97
207 99 99
213 99 100
214 97 100
216 99 99
237 93 100
296 101 104
300 100 100
304 53 101
307 99 103
334 95 104
339 100 63 98
340 105 100 99
349 95 101 102
371 100 100
377 99 100
384 102 57 88
392 99 106 99
421 99 101
422 94 99
423 99 100
426 98 101 101
429 101 96 101
435 100 100 101
TABLE C
Inhibition by Pyrrolopyrimidine Compounds of TTK, CLK1, CLK2
and CAMKK2 kinase activity.
TTK CLK1 CLK2 CAMKK2
Cmpd No. (IC50, μM) (IC50, μM) (IC50, μM) (IC50, μM)
3 1.435624 0.05389
11 0.298738 0.034896
16 0.225404 0.025999
17 0.082369 0.00433
38 0.014 0.267 0.008168 0.728
55 0.013312
67 0.016027
79 0.002379 0.058587 0.001911 0.034
89 <1.5e−003 0.041473 0.004557
90 0.001675 0.12394 0.003497
101 0.002128 0.099779 0.003377 0.501
118 0.005136 0.002294
132 0.004116 0.225986 0.029057
134 0.001678 0.130033 0.00227
145 0.002451 0.219809 0.040123
146 0.002121
152 0.00296
171 0.001471 0.082812 0.002317
191 0.003653 0.172406 0.009409
237 0.008062 0.237221 0.010372
300 0.004536
304 0.00235
334 0.001418
339 0.007004 0.526142 0.005915
349 0.001145 0.059278 0.001429
421 0.084639 0.002095
422 0.011578 0.504877 0.012494
423 0.001904 0.097765 0.003294
Conclusion.
Tables B and C show that Pyrrolopyrimidine Compounds, as described herein, inhibit the kinase activity of TTK, CLK1, and CLK2. In some embodiments, the Pyrrolopyrimidine Compounds also inhibit the kinase activity of CAMKK2.
CELL ASSAYS
Breast Cancer Cell Line Growth Inhibition.
The 49 breast cancer cell lines used in the study are shown in Table 1. The luminal and basal subtype classification was based upon public information that was verified internally. The estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status of each cell line was based upon public information that was verified internally.
TABLE 1
Breast Cancer Cell Lines
Cell Line Subtype1 Subtype2 Vendor Media
AU565 Luminal Her2+ ATCC RPMI + 10% FBS
BT-20 Basal TN ATCC DMEM + 10% FBS
BT-474 Luminal Her2+ ATCC RPMI + 10% FBS
BT-483 Luminal ER+/PR+ ATCC RPMI + 10% FBS
BT-549 Basal TN ATCC RPMI + 10% FBS
CAL-120 Basal TN DSMZ DMEM + 10% FBS
CAL-148 Luminal TN DSMZ DMEM + 10% FBS
CAL-51 Basal TN DSMZ DMEM + 10% FBS
CAL-85-1 Basal TN DSMZ DMEM + 10% FBS
CAMA-1 Luminal ER+/PR+ ATCC DMEM + 10% FBS
DU4475 Basal TN ATCC RPMI + 10% FBS
EFM-19 Luminal ER+/PR+ DSMZ RPMI + 10% FBS
EFM-192A Luminal Her2+ DSMZ RPMI + 10% FBS
EVSA-T Luminal ER+/PR+ DSMZ DMEM + 10% FBS
HCC1143 Basal TN ATCC RPMI + 10% FBS
HCC1187 Basal TN ATCC RPMI + 10% FBS
HCC1419 Luminal Her2+ ATCC RPMI + 10% FBS
HCC1428 Luminal ER+/PR+ ATCC RPMI + 10% FBS
HCC1500 Luminal ER+/PR+ ATCC RPMI + 10% FBS
HCC1569 Basal Her2+ ATCC RPMI + 10% FBS
HCC1806 Basal TN ATCC RPMI + 10% FBS
HCC1937 Basal TN ATCC RPMI + 10% FBS
HCC1954 Basal Her2+ ATCC RPMI + 10% FBS
HCC202 Luminal Her2+ ATCC RPMI + 10% FBS
HCC38 Basal TN ATCC RPMI + 10% FBS
HCC70 Basal TN ATCC RPMI + 10% FBS
HCC2157 Basal TN ATCC RPMI + 10% FBS
HDQ-P1 Basal TN DSMZ DMEM + 10% FBS
HS578T Basal TN ATCC RPMI + 10% FBS
JIMT-1 Basal Her2+ DSMZ DMEM + 10% FBS
KPL-1 Luminal ER+/PR+ DSMZ DMEM + 10% FBS
MB157 Basal TN ATCC DMEM + 10% FBS
MCF7 Luminal ER+/PR+ NCI RPMI + 10% FBS
MCF10A Basal TN ATCC RPMI + 10% FBS
MCF12A Basal TN ATCC DMEM + 10% FBS
MDA-MB-134-VI Luminal ER+/PR+ ATCC DMEM + 10% FBS
MDA-MB-157 Basal TN ATCC DMEM + 10% FBS
MDA-MB-175-VII Luminal ER+/PR+ ATCC RPMI + 10% FBS
MDA-MB-231 Basal TN ATCC RPMI + 10% FBS
MDA-MB-361 Luminal Her2+ ATCC DMEM + 10% FBS
MDA-MB-415 Luminal ER+/PR+ ATCC DMEM + 10% FBS
MDA-MB-436 Basal TN ATCC DMEM + 10% FBS
MDA-MB-453 Luminal Her2+ ATCC DMEM + 10% FBS
MDA-MB-468 Basal TN ATCC DMEM + 10% FBS
MFM-223 Luminal ER+/PR+ DSMZ DMEM + 10% FBS
MT-3 Basal TN DSMZ RPMI + 10% FBS
SK-BR-3 Luminal Her2+ ATCC RPMI + 10% FBS
T47D Luminal ER+/PR+ ATCC RPMI + 10% FBS
UACC-812 Luminal Her2+ ATCC DMEM + 10% FBS
UACC-893 Luminal Her2+ ATCC DMEM + 10% FBS
ZR-75-1 Luminal ER+/PR+ ATCC RPMI + 10% FBS
ZR-75-30 Luminal Her2+ ATCC RPMI + 10% FBS
ATCC = American Type Culture Collection;
DMEM = Dulbecco's Modified Eagle's Medium;
DSMZ = Deutsche Sammlung von. Mikroorganismen and Zellkulturen;
ER = estrogen receptor;
FBS = fetal bovine serum;
HER2 = human epidermal growth factor receptor 2;
NCI = National Cancer Institute;
PR = progesterone receptor;
TN = triple negative breast cancer: ER−, PR−, and HER2−.
Experimental Procedures.
All breast cancer cell lines were maintained and tested in the culture media indicated in Table 1. The seeding density for each cell line was optimized to ensure assay linearity in 384-well plates. Increasing concentrations of compound were spotted via an acoustic dispenser (EDC ATS-100) into an empty 384-well plate. Compound was spotted in a 10-point serial dilution fashion (3-fold dilution) in duplicate within the plate. The dimethyl sulfoxide (DMSO) concentration was kept constant for a final assay concentration of 0.1% DMSO. Plates were replicated for use against different cell lines and testing periods. After compound plate replication, all plates were sealed (Agilent ThermoLoc) and stored at −20° C. for up to 1 month. When ready for testing, plates were removed from the freezer, thawed, and unsealed just prior to the addition of the test cell. Prior to testing, cells were grown and expanded in culture flasks to provide sufficient amounts of starting material. Cells were then diluted to their desired densities and added directly to the compound-spotted 384-well plates. Cells were allowed to grow for 96 hours at 37° C./5% CO2. At the time of setup (t0), initial cell number was assessed via a viability assay (Cell Titer-Glo) and read for luminescence. After 96 hours, viability of compound-treated cells was assessed via Cell Titer-Glo and read for luminescence.
Cell lines were assayed for growth inhibition by the Pyrrolopyrimidine Compounds for at least two independent tests. To ensure a comparable compound response throughout the assay period to complete all 49 cell lines, a control cell line (A549) was included in each of the assays. All data was normalized and represented as a percentage of the DMSO-treated control cells. Results were then expressed as an IC50 (Table 2). In addition, GI50 was calculated (Table 3).
All statistical analyses were implemented using R software (R Development Core Team, 2009).
Determination of Inhibitory Concentration and Growth Inhibition (IC50 and GI50).
IC50 is the concentration of the compound when Y=50% of DMSO control. GI50 is the concentration of the compound when Y=(YMax+Yt0)/2. All growth inhibition curves were processed and evaluated using Activity Base XE (IDBS).
TABLE 2
Growth Inhibition IC50 (μM)
Cmpd Cmpd Cmpd Cmpd Cmpd Cmpd
Cell Line 79 101 125 38 152 3
AU565 0.019 0.213 0.021 0.038 0.047 1.099
BT-20 0.053 0.897 0.044 0.049 0.094 0.608
BT-474 0.358 10.000 0.595 10.000 5.423 16.345
BT-483 10.000 10.000 3.402 10.000 10.000 10.000
BT-549 0.013 0.292 0.066 0.051 0.079 0.180
CAL-120 0.592 10.000 0.272 10.000 4.638 10.000
CAL-148 0.003 0.074 0.168 0.065 0.069
CAL-51 0.001 0.069 0.010 0.010 0.018 0.009
CAL-85-1 0.029 0.423 0.093 0.052 0.087 0.076
CAMA-1 10.000 10.000 0.763 10.000 10.000 10.706
DU4475 0.087 0.248 0.246 2.253 0.244 0.560
EFM-19 0.083 0.263 0.181 0.196 0.221 0.730
EFM-192A 2.085 10.000 1.279 10.000 5.042 10.000
EVSA-T 0.311 9.438 0.206 10.000 1.720
HCC1143 0.308 0.685 0.481 0.579 0.711 17.483
HCC1187 0.002 0.119 0.031 0.042 0.066 0.881
HCC1419 10.000 10.000 2.511 10.000 10.000
HCC1428 0.523 8.149 0.472 10.000 0.945 4.967
HCC1500 10.000 10.000 2.279 10.000 10.000 13.857
HCC1569 0.170 0.327 0.408 0.288 1.037 5.434
HCC1806 0.001 0.062 0.011 0.009 0.022
HCC1937 0.695 10.000 0.311 10.000 5.646 10.000
HCC1954 0.016 0.258 0.068 0.039 0.102 0.482
HCC202 0.216 2.104 0.190 3.072 0.462 15.961
HCC2157 0.120
HCC38 0.001 0.052 0.012 0.011 0.021 0.047
HCC70 0.047 6.705 0.268 1.300 1.023 1.950
HDQ-P1 0.128 1.775 0.083 0.326 0.204
HS578T 0.012 0.221 0.041 0.052 0.059 0.183
JIMT-1 5.336 9.074 0.165 0.111 0.215
KPL-1 0.429 6.464 0.064 5.202 0.318 0.693
MB157 0.351 9.404 0.419 10.000 5.318
MCF10A 17.449
MCF12A 3.151
MCF7 0.002 0.079 0.012 0.012 0.025 0.170
MDA-MB- 10.000 10.000 3.168 10.000 10.000 1.386
134-VI
MDA-MB- 1.636 10.000 0.631 6.290 10.000 0.695
157
MDA-MB- 10.000 10.000 2.843 10.000 10.000 8.497
175-VII
MDA-MB- 0.004 0.135 0.031 0.024 0.054 0.038
231
MDA-MB- 2.830 10.000 1.472 10.000 10.000 18.751
361
MDA-MB- 10.000 10.000 5.512 10.000 10.000 13.454
415
MDA-MB- 1.108 4.194 0.510 7.821 0.718 2.100
436
MDA-MB- 0.316 10.000 0.668 10.000 0.443 2.788
453
MDA-MB- 0.001 0.096 0.024 0.027 0.057 0.032
468
MFM-223 0.355 0.984 0.172 1.879 0.429
MT-3 10.000 10.000 8.500 10.000 10.000
SK-BR-3 0.323 0.570 0.272 0.578 0.417 3.688
T47D 0.419 10.000 0.336 1.651 0.715 0.418
UACC-812 4.375 8.030 0.296 10.000 0.888 1.794
UACC-893 10.000 10.000 0.787 10.000 1.833
ZR-75-1 10.000 10.000 3.314 10.000 10.000 6.386
ZR-75-30 1.268 3.413 0.715 10.000 1.576 30.000
TABLE 3
Growth inhibition GI50 (μM)
Cmpd Cmpd Cmpd Cmpd Cmpd Cmpd
Cell Line 79 101 125 38 152 3
AU565 0.005 0.100 0.016 0.011 0.024 0.426
BT-20 0.019 0.553 0.028 0.028 0.057 0.289
BT-474 0.106 7.373 10.000 0.202 0.645 6.016
BT-483 n/a n/a n/a n/a n/a 0.704
BT-549 0.006 0.166 0.034 0.043 0.055 0.085
CAL-120 0.521 10.000 10.000 0.245 3.462 10.000
CAL-148 0.002 0.048 0.047 0.060 0.052
CAL-51 0.001 0.059 0.009 0.009 0.016 0.008
CAL-85-1 0.014 0.218 0.029 0.061 0.055 0.025
CAMA-1 1.066 0.628 0.590 0.261 0.308 4.895
DU4475 0.004 0.046 0.038 0.058 0.059 0.082
EFM-19 0.006 0.051 0.035 0.047 0.065 0.067
EFM-192A 0.309 0.451 0.294 0.424 0.411 10.000
EVSA-T 0.121 6.665 6.000 0.130 0.557
HCC1143 0.093 0.325 0.215 0.275 0.374 0.286
HCC1187 0.002 0.083 0.027 0.021 0.044 0.470
HCC1419 1.684 6.162 10.000 1.008 1.491
HCC1428 0.215 0.516 0.326 0.206 0.288 1.086
HCC1500 0.058 0.090 0.103 0.112 0.103 0.053
HCC1569 0.036 0.116 0.088 0.140 0.102 0.073
HCC1806 0.001 0.057 0.008 0.010 0.020
HCC1937 0.245 8.128 6.376 0.161 0.426 7.460
HCC1954 0.007 0.159 0.027 0.041 0.061 0.131
HCC202 0.009 0.052 0.028 0.018 0.044 15.026
HCC2157 0.024
HCC38 0.001 0.040 0.009 0.010 0.017 0.017
HCC70 0.005 0.128 0.047 0.080 0.086 0.442
HDQ-P1 0.037 0.890 0.106 0.046 0.108
HS578T 0.010 0.203 0.047 0.038 0.055 0.104
JIMT-1 2.098 2.498 0.061 0.116 0.154
KPL-1 0.136 2.884 0.126 0.034 0.108 0.245
MCF10A 0.426
MCF12A 0.486
MB157 0.026 0.425 0.116 0.067 0.123
MCF7 0.001 0.070 0.011 0.010 0.021 0.124
MDA-MB- n/a n/a n/a n/a n/a 0.874
134-VI
MDA-MB- 0.018 5.117 0.114 0.176 0.110 0.225
157
MDA-MB- 0.700 0.534 5.285 0.523 1.087 0.400
175-VII
MDA-MB- 0.003 0.104 0.019 0.022 0.041 0.022
231
MDA-MB- 0.043 0.110 0.091 0.231 0.143 5.481
361
MDA-MB- 10.000 9.995 10.000 0.441 10.000 11.707
415
MDA-MB- 0.433 1.020 0.999 0.289 0.327 1.382
436
MDA-MB- 0.212 5.387 10.000 0.475 0.390 0.799
453
MDA-MB- 0.001 0.083 0.023 0.020 0.049 0.027
468
MFM-223 0.009 0.050 0.043 0.035 0.058
MT-3 1.093 1.117 5.757 1.659 10.000
SK-BR-3 0.051 0.102 0.081 0.082 0.124 1.181
T47D 0.040 0.386 0.081 0.106 0.140 0.162
UACC-812 0.369 0.748 0.319 0.110 0.201 0.842
UACC-893 n/a n/a n/a n/a n/a
ZR-75-1 0.002 0.039 0.032 0.050 0.062 1.136
ZR-75-30 n/a n/a n/a n/a n/a 11.619
n/a: not applicable
Conclusions.
As can be seen from Tables 2 and 3, Pyrrolopyrimidine Compounds inhibited breast cancer cell line growth, as measured by IC50 and GI50. Cell proliferation inhibition was shown in TNBC, as well as ER+/PR+ and Her2+, to variying degrees.
Non-Small Cell Lung Cancer Cell Line Growth Inhibition.
Sixteen non small cell lung cancer (NSCLC) cell lines were purchased from the American Tissue Culture Collection and maintained in growth media consisting of 90% RPMI1640 (Invitrogen) and 10% fetal bovine serum (Hyclone). All cells were cultured at 37° C. in 95% air and 5% CO2. Cells were plated at optimal density for each cell line (see Table 5) per well in a 96-well plate in 100 μL of growth media. After overnight culture, compound stock solutions (30 mM) were diluted serially in DMSO, further diluted in growth media, and was added to each well as a 10× concentrated solution in a volume of 11 μL, mixed, and allowed to incubate with cells. The compound vehicle (DMSO) was maintained at a final concentration of 0.2% in all wells. After 72 hrs, 100 μL of Cell Titer Glo solution (Promega) were added to each well of the 96-well plate. The plate was placed on a shaker for 2 minutes. After 10 minutes incubation, luminescence signal was detected with Envision microplate reader (Perkin Elmer). The IC50 values were calculated as the concentration of compound at which the level of luminescence signal was reduced to 50% of the signal window. Table 4 shows the results for Compound 3. Compounds show or will show an IC50 value ranging from 0.01-30 μM in this assay.
TABLE 4
Growth Inhibition IC50 Values and Growth Conditions
Plating Average
Cell Line Density IC50 (μM) SD
H1734 16000 0.91 0.59
H1838 12000 16.11 19.65
H2228 20000 1.58 0.41
H441 16000 2.10 0.32
H1437 12000 0.39 0.33
Hop62 2800 0.05 N/A
H1650 8000 0.62 0.02
HOP92 6000 1.27 0.62
H520 32000 1.45 0.18
H1299 2800 0.36 0.34
H2291 16000 16.29 19.39
H1563 6000 1.77 0.09
SK-LU-1 5000 0.83 0.10
SW1573 5000 0.96 0.23
A549 2500 0.05 0.04
H460 1500 0.04 0.01
Conclusion.
Pyrrolopyrimidine Compounds demonstrated potent growth inhibition over a panel of non small cell lung cancer cell (NSCLC) lines profiled, as shown in Table 4. The majority of NSCLC lines (14 out of 16) are sensitive to growth inhibition by Pyrrolopyrimidine Compounds (for example, Compound 3) with a IC50 values ≦2 μM.
Multiplexed Cytotoxicity Assay.
Cells were grown in RPMI1640, 10% FBS, 2 mM L-alanyl-L-Glutamine, 1 mM Na pyruvate or a special medium in a humidified atmosphere of 5% CO2 at 37° C. Cells were seeded into 384-well plates and incubated in a humidified atmosphere of 5% CO2 at 37° C. Compounds were added 24 hours post cell seeding. At the same time, a time zero untreated cell plate was generated. After a 72 hour incubation period, cells were fixed and stained with fluorescently labeled antibodies and nuclear dye to allow visualization of nuclei, apoptotic cells and mitotic cells. Apoptotic cells were detected using an anti-active caspase-3 antibody. Mitotic cells were detected using an anti phospho-histone-3 antibody. Compounds were serially diluted 3.16-fold and assayed over 10 concentrations in a final assay concentration of 0.1% DMSO from the highest test concentration of 10 μM. Automated fluorescence microscopy was carried out using a GE Healthcare IN Cell Analyzer 1000, and images were collected with a 4× objective.
Data Analysis.
Twelve bit tiff images were acquired using the InCell Analyzer 1000 3.2 and analyzed with Developer Toolbox 1.6 software. Cell proliferation was measured by the signal intensity of the incorporated nuclear dye. Results for Compound 38 are shown in Table 6. The cell proliferation assay output is referred to as the relative cell count. To determine the cell proliferation end point, the cell proliferation data output is transformed to percentage of control (POC) using the following formula:
POC=relative cell count(compound wells)/relative cell count(vehicle wells)×100
Relative cell count IC50 is the test compound concentration at 50% of maximal possible response relative to the DMSO control. GI50 is the concentration needed to reduce the observed growth by half. This is the concentration that inhibits the growth to the level midway between growth in untreated cells and the number of cells seeded in the well (Time zero value). The IC50 values were calculated using nonlinear regression to fit data to a sigmoidal 4 point, 4 parameter One-Site dose response model, where:
y(fit)=A+[(B−A)/(1+((C/x)^D))].
The activated caspase-3 marker labels cells from early to late stage apoptosis. The output is shown as a fold increase of apoptotic cells over vehicle background normalized to the relative cell count in each well. Concentrations of test compound that cause a 5-fold induction in the caspase-3 signal (Cal_X5) indicate significant apoptosis induction. The maximal induction of caspase 3 by compound in comparison with DMSO control is reported as Max_Fold_Change.
TABLE 5
Cell lines
Cell line Tumor Type Subtype Classification
5637 Bladder
639-V Bladder
647-V Bladder
BFTC-905 Bladder
HT1197 Bladder
HT1376 Bladder
J82 Bladder
SCaBER Bladder
T24 Bladder
TCCSUP Bladder
UM-UC-3 Bladder
AU565 Breast Luminal Luminal
BT-20 Breast Basal Basal
BT-474 Breast Luminal Luminal
BT-549 Breast Basal Basal
CAMA-1 Breast Luminal Luminal
EFM-19 Breast Luminal Luminal
HS578T Breast Basal Basal
KPL-1 Breast Luminal Luminal
MCF7 Breast Luminal Luminal
MDA-MB-231 Breast Basal Basal
MDA-MB-436 Breast Basal Basal
MDA-MB-453 Breast Luminal Luminal
MDA-MB-468 Breast Basal Basal
MT-3 Breast Basal Basal
SK-BR-3 Breast Luminal Luminal
T47D Breast Luminal Luminal
A172 CNS Glioblastoma Glioblastoma
BE(2)C CNS
CCF-STTG1 CNS Astrocytoma Astrocytoma
CHP-212 CNS
D-283MED CNS
Daoy CNS Medullo- Medulloblastoma
blastoma
DBTRG-05MG CNS Glioblastoma Glioblastoma
DK-MG CNS Glioblastoma Glioblastoma
H4 CNS Neuroglioma Neuroglioma
MC-IXC CNS
SK-N-AS CNS
SK-N-DZ CNS
SK-N-FI CNS
SNB-19 CNS Glioblastoma Glioblastoma
SW1088 CNS Astrocytoma Astrocytoma
SW1783 CNS Astrocytoma Astrocytoma
T98G CNS Glioblastoma Glioblastoma
U-138MG CNS Glioblastoma Glioblastoma
U-87-MG CNS Astrocytoma Astrocytoma
COLO-201 Colon Large Intestine
COLO-205 Colon Large Intestine
COLO-320DM Colon Large Intestine
COLO-320-HSR Colon Large Intestine
DLD-1 Colon Large Intestine
HCT-116 Colon Large Intestine
HCT-15 Colon Large Intestine
HCT-8 Colon Large Intestine
HT29 Colon Large Intestine
LS-1034 Colon Large Intestine
LS-174T Colon Large Intestine
NCI-H508 Colon Large Intestine
NCI-H747 Colon Large Intestine
RKO Colon Large Intestine
RKO-AS45-1 Colon Large Intestine
RKO-E6 Colon Large Intestine
SW1417 Colon Large Intestine
SW403 Colon Large Intestine
SW48 Colon Large Intestine
SW480 Colon Large Intestine
SW620 Colon Large Intestine
SW837 Colon Large Intestine
SW948 Colon Large Intestine
WiDr Colon Large Intestine
AGS Colon/GI Stomach
HS746T Colon/GI Stomach
KATOIII Colon/GI Stomach
OE19 Colon/GI Oesophagus
SNU-1 Colon/GI Stomach
SNU-16 Colon/GI Stomach
SNU-5 Colon/GI Stomach
SW1463 Colon Rectum
BHT-101 Endocrine Thyroid
CAL-62 Endocrine Thyroid
CGTH-W-1 Endocrine Thyroid
NCI-H295 Endocrine Adrenal cortex
SW13 Endocrine Adrenal gland
SW579 Endocrine Thyroid
Y79 Eye Retino-
blastoma
AN3 CA Female GU Uterus
BeWo Female GU Placenta
C-33-A Female GU Cervix
C4-1 Female GU Cervix
C4-2 Female GU Cervix
Caov-3 Female GU Ovary
DoTc2-4510 Female GU Cervix
ES-2 Female GU Ovary
HEC-1-A Female GU Uterus
HeLa Female GU Cervix
HT3 Female GU Cervix
JAR Female GU Placenta
JEG-3 Female GU Placenta
KLE Female GU Uterus
Ovcar-3 Female GU Ovary
RL95-2 Female GU Uterus
SiHa Female GU Cervix
SK-OV-3 Female GU Ovary
SW954 Female GU Vulva
SW962 Female GU Vulva
CAL-27 Head and Neck Tongue
Detroit562 Head and Neck Pharynx
FADU Head and Neck Pharynx
OE21 Head and Neck
OE33 Head and Neck Oesophagus
SCC-25 Head and Neck Tongue
SCC-4 Head and Neck Tongue
SCC-9 Head and Neck Tongue
L428 Hodgkin's
lymphoma
RPMI-6666 Hodgkin's
lymphoma
769-P Kidney
786-0 Kidney
A498 Kidney
ACHN Kidney
CAKI-1 Kidney
CAKI-2 Kidney
G-401 kidney
G-402 Kidney
SK-NEP-1 Kidney
ARH-77 Myeloma Plasma cell
BV-173 Leukemia CML
CCRF-CEM Leukemia myelomono- T-ALL
blastic
CEM-C1 Leukemia ALL
CML-T1 Leukemia CML
EM-2 Leukemia CML
HEL-92-1-7 Leukemia Erythro-
leukemia
J-RT3-T3-5 Leukemia Acute T cell
Jurkat Leukemia Acute T cell
K-562 Leukemia CML CML
MEG-01 Leukemia CML
MOLT-16 Leukemia ALL
MOLT-3 Leukemia ALL
MV-4-11 Leukemia B
myelo-
monocytic
MX1 Leukemia APML
NALM-6 Leukemia B cell
precursor
THP-1 Leukemia AML AML
HepG2 Liver
HLE Liver
HLF Liver
HuCCT1 Liver
HUH-6-clone5 Liver
OCUG-1 Liver
SNU-423 Liver
A427 Lung
A549 Lung NSCLC
Calu-1 Lung SQCC NSCLC
Calu-6 Lung Anaplastic NSCLC
ChaGo-K-1 Lung Broncho-
genic
COR-L105 Lung
COR-L23 Lung NSCLC
DMS-114 Lung SCLC SCLC
DMS-273 Lung SCLC
DMS-53 Lung SCLC SCLC
NCI-H292 Lung Mucoepidermoid
NCI-H441 Lung NSCLC NSCLC
NCI-H446 Lung SCLC
NCI-H460 Lung NSCLC
NCI-H520 Lung NSCLC NSCLC
NCI-H596 Lung NSCLC NSCLC
NCI-H661 Lung NSCLC
NCI-H69 Lung SCLC
SHP-77 Lung SCLC
SK-MES-1 Lung SQCC SQCC
SW900 Lung SQCC NSCLC
Wi38 Lung Normal Normal Fibroblasts
fibroblasts
BC-1 Lymphoma
CRO-AP2 Lymphoma B cell
Daudi Lymphoma BL BL
DB Lymphoma Large cell DLBCL
DOHH-2 Lymphoma B cell FL
EB-3 Lymphoma BL
HT Lymphoma Diffuse DLBCL
mixed
MHH-PREB-1 Lymphoma B cell Lymphoblastic
Raji Lymphoma BL BL
Ramos RA1 Lymphoma BL BL
SKO-007 Lymphoma B
lymphocyte
SR Lymphoma Large cell Large
immuno-
blastic
ST486 Lymphoma BL
RPMI-8226 Myeloma Plasma- B-cell
cytoma;
myeloma
U266B1 Myeloma Myeloma B-cell
AsPC-1 Pancreas
BxPC-3 Pancreas
CAPAN-1 Pancreas
CAPAN-2 Pancreas
CFPAC-1 Pancreas
HPAF-II Pancreas
HS766T Pancreas
HuP-T4 Pancreas
MIA-PaCa-2 Pancreas
PANC-1 Pancreas
SU.86.86 Pancreas
YAPC Pancreas
22RV1 Prostate
BM-1604 Prostate
BPH-1 Prostate
BPH-1 Prostate
BPH-1 Prostate
DU-145 Prostate
LNCaP Prostate
PC-3 Prostate
A101D Skin Melanoma
A375 Skin Melanoma
A431 Skin SQCC
A7 Skin Melanoma
C32 Skin Melanoma
C32TG Skin Melanoma
CHL-1 Skin Melanoma
COLO-829 Skin Melanoma
HMCB Skin Melanoma
HS294T Skin Melanoma
HS695T Skin Melanoma
MALME-3M Skin Melanoma
Mewo Skin Melanoma
RPMI-7951 Skin Melanoma
SH-4 Skin Melanoma
SK-MEL-1 Skin Melanoma
SK-MEL-28 Skin Melanoma
SK-MEL-3 Skin Melanoma
A204 Soft Tissue Rhabdomyo-
sarcoma
A673 Soft Tissue Sarcoma
HOS Bone Sarcoma
HT1080 Soft Tissue Sarcoma
KHOS-240S Bone Osteo-
sarcoma
MES-SA Soft Tissue Sarcoma
MG-63 Bone Sarcoma
RD Soft Tissue Sarcoma
Saos-2 Bone Sarcoma
SJRH30 Soft Tissue Rhabdomyo-
sarcoma
SJSA-1 Bone Osteo-
sarcoma
SK-LMS-1 Soft Tissue Sarcoma
SK-UT-1 Soft Tissue Sarcoma
SW1353 Bone Sarcoma
SW684 Soft Tissue Sarcoma
SW872 Soft Tissue Sarcoma
SW982 Soft Tissue Sarcoma
TE 381.T Soft Tissue Rhabdomyo-
sarcoma
U-2-OS Bone Sarcoma
TABLE 6
Cell line screening results
GI50 IC50 Max. Fold.
Cell Line (μM) (μM) Change Cal_X
5637 0.0905 0.0946 51.0 0.1026
639-V 0.0855 0.0904 13.5 0.0540
647-V 0.1022 0.1177 12.4 0.0757
BFTC-905 0.0626 0.0649 22.1 0.0428
HT1197 1.7581 5.7255 5.5 8.8398
HT1376 0.9204 1.9883 5.3 9.1659
J82 1.0029 10.0000 4.9 10.0000
SCaBER 0.0894 0.0927 16.3 0.0581
T24 0.0941 0.0960 68.3 0.0008
TCCSUP 0.0657 0.0958 5.2 0.0974
UM-UC-3 0.1021 0.1314 70.6 0.0372
AU565 0.4598 1.2290 33.8 0.2656
BT-20 0.4591 1.2935 4.4 10.0000
BT-474 0.0837 4.3719 20.0 1.1580
BT-549 1.7310 4.8054 5.6 0.2720
CAMA-1 0.4279 1.1890 7.5 5.2170
EFM-19 0.0618 0.1036 32.5 0.0686
HS578T 10.0000 10.0000 3.8 10.0000
KPL-1 0.8217 2.4194 67.2 0.0888
MCF7 0.1287 0.8192 26.2 0.0625
MDA-MB-231 0.3690 0.7750 5.6 0.2184
MDA-MB-436 0.8881 1.8798 1.8 10.0000
MDA-MB-453 0.0810 0.1111 9.7 0.1290
MDA-MB-468 0.0928 0.1017 14.1 0.1679
MT-3 0.0395 0.0478 7.3 0.0696
SK-BR-3 0.2868 1.3152 4.4 10.0000
T47D 0.2919 1.1604 10.4 4.9403
A172 0.0457 10.0000 11.9 0.0521
BE(2)C 0.0796 0.0893 29.6 0.0468
CCF-STTG1 4.4267 5.6280 5.0 10.0000
CHP-212 0.0278 0.0364 11.4 0.0458
D-283MED 0.0584 0.0654 26.0 0.0580
Daoy 0.0887 0.1043 13.1 0.0849
DBTRG-05MG 4.2986 10.0000 4.4 10.0000
DK-MG 10.0000 10.0000 9.2 5.4460
H4 0.0718 0.0736 44.9 0.0422
MC-IXC 0.0471 0.0539 51.6 0.0439
SK-N-AS 0.4244 1.5168 14.5 0.0515
SK-N-DZ 0.1618 0.2077 34.8 0.2178
SK-N-FI 2.2181 9.5496 3.2 10.0000
SNB-19 10.0000 10.0000 1.6 10.0000
SW1088 0.0469 10.0000 13.1 0.0560
SW1783 10.0000 10.0000 3.1 10.0000
T98G 2.6239 10.0000 61.2 0.0426
U-138MG 10.0000 10.0000 4.8 10.0000
U-87-MG 0.1044 10.0000 11.2 0.0659
COLO-201 0.1052 0.1272 8.2 0.3152
COLO-205 0.0824 0.0838 182.5 0.0440
COLO-320DM 0.0927 0.1254 75.6 0.0723
COLO-320-HSR 0.1034 0.1261 37.3 0.0717
DLD-1 0.0473 0.0496 45.1 0.0338
HCT-116 0.0479 0.0488 37.9 0.0385
HCT-15 0.0531 0.0559 58.9 0.0377
HCT-8 0.0298 0.0312 282.4 0.0138
HT29 0.1156 0.1265 35.8 0.0632
LS-1034 0.1033 0.1061 6.7 0.2283
LS-174T 0.0665 0.0914 16.1 0.0479
NCI-H508 0.2291 0.5928 30.5 0.0649
NCI-H747 0.3733 1.6297 3.3 10.0000
RKO 0.0504 0.0526 35.1 0.0394
RKO-AS45-1 0.0415 0.0445 24.5 0.0371
RKO-E6 0.0513 0.0527 14.4 0.0490
SW1417 4.5665 10.0000 6.5 6.7147
SW403 0.2573 0.2969 12.2 0.4506
SW48 0.0459 0.0497 12.0 0.0623
SW480 1.0169 2.1065 25.3 3.9577
SW620 0.0572 0.0636 20.3 0.0559
SW837 0.3301 0.8362 34.9 0.0815
SW948 0.2469 0.2875 26.6 0.2257
WiDr 0.3583 0.6266 22.3 0.1700
AGS 0.0308 0.0328 12.1 0.0312
HS746T 10.0000 10.0000 2.6 10.0000
KATOIII 1.0051 1.9453 31.3 0.0715
OE19 0.0575 0.0636 33.6 0.0524
SNU-1 0.2788 0.4798 12.6 0.0473
SNU-16 0.1487 0.2269 3.9 10.0000
SNU-5 5.9807 10.0000 2.3 10.0000
SW1463 5.0067 10.0000 4.3 10.0000
BHT-101 0.3120 0.4093 64.6 0.1877
CAL-62 0.0972 0.0987 35.2 0.0450
CGTH-W-1 0.1027 0.1096 32.2 0.0429
NCI-H295 10.0000 10.0000 3.1 10.0000
SW13 0.1621 0.2426 19.3 0.0657
SW579 2.6704 10.0000 6.6 0.0772
Y79 0.1843 0.2576 6.4 1.6819
AN3 CA 0.5117 1.1664 14.1 3.7957
BeWo 0.5064 0.7466 5.2 9.4738
C-33-A 0.0745 0.1220 33.7 0.3941
C4-1 0.0804 0.1144 20.8 0.0827
C4-2 0.2487 0.4270 16.3 1.1314
Caov-3 0.0666 0.1061 4.0 10.0000
DoTc2-4510 0.3552 0.7875 12.9 0.7698
ES-2 0.0915 0.0936 33.3 0.0487
HEC-1-A 0.1656 0.4534 4.3 10.0000
HeLa 0.3882 0.6010 6.5 0.8340
HT3 1.3798 2.5017 6.2 7.0920
JAR 0.0495 0.0519 24.8 0.0576
JEG-3 0.0859 0.0954 15.8 0.0726
KLE 2.3130 6.4698 15.4 4.5020
Ovcar-3 0.4434 0.8643 135.6 0.7343
RL95-2 0.0455 0.0649 4.0 10.0000
SiHa 10.0000 10.0000 6.0 8.3919
SK-OV-3 10.0000 10.0000 8.0 1.8718
SW954 0.0866 0.0887 11.0 0.1179
SW962 10.0000 10.0000 3.6 10.0000
CAL-27 0.0538 0.0567 15.5 0.0493
Detroit562 0.0471 0.0537 22.6 0.0553
FADU 0.1223 0.1661 8.0 0.0792
OE21 0.0651 0.0682 12.3 0.0738
OE33 0.1965 0.3052 8.8 0.2006
SCC-25 0.0673 0.0731 19.5 0.0894
SCC-4 8.3155 10.0000 3.0 10.0000
SCC-9 0.2650 0.5288 17.0 0.2767
L428 3.2804 4.5993 4.8 10.0000
RPMI-6666 0.1481 0.1535 7.8 0.2252
769-P 0.2663 0.3597 4.9 10.0000
786-0 0.1115 0.1199 22.1 0.0690
A498 0.4915 1.3982 7.3 0.0728
ACHN 0.3960 0.8495 60.4 0.0460
CAKI-1 0.1284 10.0000 3.9 10.0000
CAKI-2 10.0000 10.0000 3.0 10.0000
G-401 0.0794 0.0817 12.7 0.7392
G-402 0.0378 0.0431 16.3 0.0566
SK-NEP-1 0.1270 0.1681 17.4 0.3116
ARH-77 0.0594 0.0618 26.4 0.0525
BV-173 0.0444 0.0454 29.4 0.0427
CCRF-CEM 0.0813 0.0819 16.6 0.0617
CEM-C1 0.4524 0.4805 18.3 0.0529
CML-T1 0.0689 0.0716 29.8 0.0430
EM-2 0.0903 0.0988 13.5 0.0766
HEL-92-1-7 0.5351 0.6301 20.7 1.1545
J-RT3-T3-5 0.0463 0.0534 13.4 0.0286
Jurkat 0.0501 0.0551 19.0 0.0460
K-562 2.6980 4.7723 13.7 0.6802
MEG-01 2.1931 3.8366 3.1 10.0000
MOLT-16 0.0383 0.0388 12.0 0.0798
MOLT-3 0.1187 0.4689 4.5 10.0000
MV-4-11 0.0906 0.0940 14.8 0.3032
MX1 0.0576 0.0589 44.7 0.0394
NALM-6 0.0547 0.0560 72.7 0.0359
THP-1 10.0000 10.0000 4.8 10.0000
HepG2 0.1366 0.2124 18.1 0.0853
HLE 0.1020 0.1067 4.5 10.0000
HLF 0.1232 0.1817 29.3 0.0430
HuCCT1 1.4582 2.6967 13.2 0.0503
HUH-6-clone5 0.1433 0.1756 31.2 0.1025
OCUG-1 1.2036 3.9346 11.5 0.2126
SNU-423 10.0000 10.0000 3.2 10.0000
A427 0.0794 0.1168 15.7 0.0238
A549 0.0528 0.0602 61.6 0.0287
Calu-1 2.9029 9.0678 11.7 0.1295
Calu-6 4.6564 8.1661 5.2 8.9974
ChaGo-K-1 0.1465 0.3720 4.4 10.0000
COR-L105 0.1447 0.5875 4.7 10.0000
COR-L23 0.1414 0.1531 7.2 0.1411
DMS-114 1.3925 4.6519 4.0 10.0000
DMS-273 0.0674 0.0690 15.9 0.0568
DMS-53 1.7366 6.6828 48.7 0.2879
NCI-H292 0.0817 0.0921 30.5 0.0722
NCI-H441 0.8207 3.0855 4.2 10.0000
NCI-H446 0.3539 0.4244 6.5 1.9460
NCI-H460 0.0870 0.0877 98.0 0.0407
NCI-H520 0.3189 0.4497 7.9 1.2581
NCI-H596 0.2824 10.0000 2.2 10.0000
NCI-H661 1.7213 4.2789 10.7 0.0680
NCI-H69 NaN NaN 3.0 10.0000
SHP-77 0.1818 0.2783 6.9 1.9384
SK-MES-1 0.4135 0.9021 18.5 0.1941
SW900 10.0000 10.0000 2.1 10.0000
Wi38 0.6851 1.8760 6.8 0.0772
BC-1 0.0621 0.0655 60.2 0.0548
CRO-AP2 0.0458 0.0494 87.5 0.0602
Daudi 0.0953 0.0974 14.8 0.0573
DB 0.0758 0.0833 40.8 0.0742
DOHH-2 0.0677 0.0714 17.5 0.0971
EB-3 0.2738 0.4248 8.4 0.2986
HT 0.1784 0.2437 3.1 10.0000
MHH-PREB-1 0.0637 0.0653 44.2 0.0422
Raji 0.0511 0.0544 21.3 0.0504
RamosRA1 0.0871 0.0881 50.0 0.0617
SKO-007 0.9528 1.2076 10.7 2.0090
SR 0.0855 0.0867 33.0 0.0603
ST486 0.0361 0.0401 27.5 0.0584
RPMI-8226 0.1150 0.1836 13.8 0.5722
U266B1 0.1590 0.3756 7.6 4.1758
AsPC-1 1.5312 10.0000 6.9 5.2046
BxPC-3 0.0814 0.1361 8.8 0.0630
CAPAN-1 0.9358 2.4121 3.1 10.0000
CAPAN-2 0.2937 10.0000 28.8 0.0583
CFPAC-1 10.0000 10.0000 15.2 0.0568
HPAF-II 0.2492 0.3684 11.5 0.2588
HS766T 10.0000 10.0000 5.7 0.7781
HuP-T4 0.1092 0.1366 12.6 0.2143
MIA-PaCa-2 0.3260 0.5436 15.6 0.0639
PANC-1 3.3504 9.5585 3.4 10.0000
SU.86.86 0.8641 1.9177 17.9 0.0704
YAPC 0.8691 3.1871 51.2 0.0322
22RV1 0.1405 0.2485 39.2 0.0361
BM-1604 1.1194 2.0149 20.8 0.2011
BPH-1 0.1498 0.1669 7.5 0.2422
DU-145 0.0958 0.0991 394.0 0.0382
LNCaP 9.6042 10.0000 2.9 10.0000
PC-3 1.2048 2.3542 14.1 1.2528
A101D 0.3510 0.8607 18.1 0.1754
A375 0.0460 0.0475 38.5 0.0356
A431 0.0924 0.0986 13.5 0.1298
A7 0.1262 0.2490 9.0 0.0468
C32 1.1087 10.0000 13.0 1.9676
C32TG 0.8305 2.0288 15.1 0.2294
CHL-1 0.0972 0.1044 41.1 0.0180
COLO-829 2.0590 8.5007 6.8 0.7345
HMCB 0.0964 0.0988 20.4 0.0619
HS294T 0.0970 0.1178 16.5 0.0567
HS695T 0.7708 3.0838 18.4 3.0148
MALME-3M 1.6636 10.0000 1.8 10.0000
Mewo 10.0000 10.0000 4.5 10.0000
RPMI-7951 0.0999 0.1052 5.1 0.2834
SH-4 0.0565 0.3220 9.9 0.0396
SK-MEL-1 10.0000 10.0000 1.9 10.0000
SK-MEL-28 10.0000 10.0000 6.6 0.2632
SK-MEL-3 2.5742 10.0000 4.1 10.0000
A204 0.0579 0.1457 9.2 0.0629
A673 0.0560 0.0735 4.3 10.0000
HOS 0.0737 0.0756 85.6 0.0362
HT1080 0.0855 0.0899 17.5 0.0672
KHOS-240S 0.0991 0.1100 16.3 0.0789
MES-SA 0.0354 0.0379 47.3 0.0241
MG-63 2.0387 4.6830 7.5 0.4768
RD 0.4567 0.7541 26.7 0.1603
Saos-2 1.8273 4.5508 3.6 10.0000
SJRH30 0.5334 1.3424 6.9 0.0992
SJSA-1 10.0000 10.0000 89.2 0.0538
SK-LMS-1 4.4020 10.0000 4.5 10.0000
SK-UT-1 0.2891 0.9592 10.1 0.3581
SW1353 10.0000 10.0000 8.3 0.2769
SW684 10.0000 10.0000 3.0 10.0000
SW872 0.1001 0.1204 53.3 0.0551
SW982 3.6570 10.0000 2.7 10.0000
TE 381.T 4.8712 10.0000 6.8 0.2981
U-2-OS 0.0821 0.0887 35.6 0.0438
Note: NaN: variable data
Conclusion.
As shown in Table 6 and FIGS. 1 and 2, Pyrrolopyrimidine Compounds (exemplified by Compound 38) showed anti-proliferative activity in a variety of cancers, comprising solid tumors (FIG. 1), for example, cancers of the bladder, breast, CNS, colon, endocrine, female GU, head and neck, kidney, liver, lung, pancreas, prostate, skin, bone and soft-tissue, and hematological cancers (FIG. 2), for example, lymphomas, leukemias and multiple myeloma.
GBM Cancer Stem Cell Viability Assay.
Five high grade glioblastoma-derived tumor cultures in defined serum-free medium that enriches the GBM-CSC tumor subfraction were established, as described previously [Mao P, et al. Proc Nat Acad Sci 2013; 110(21): 8644-9]. Clinical diagnoses and stem cell marker analyses were performed. The cancer stem cells (CSCs) (8311, 81611, 32612, 1912, and 52810), were plated in a 20 μL/well volume of serum-free growth medium at a density of 800 cells/well in a 384-well format. GBM CSCs were mechanically-dissociated by trituration prior to counting and plating. As a normal cell control, 1200 HUVECs were plated in 20 μL per well of a 384-well plate in Endothelial Growth Media Microvascular-2. After 1 day of cultivation, 20 μL/well of respective fresh medium for each cell type was added and the cells were treated with Pyrrolopyrimidine Compounds at multiple concentrations or 0.04 μL DMSO for 3 days under 5% CO2/37° C. culture conditions. After 3 days of compound treatment, cells were lysed through the addition of 30 μL of CellTiter-Glo (CTG) reagent to evaluate relative cell density. The plate was placed at room temperature for 30 minutes after which luminescent signal was monitored.
Results.
Table 7 summarizes the GBM subtype affiliation of each GBM-CSC model utilized. The impact of Pyrrolopyrimidine Compounds on the growth of GBM-CSCs was tested under defined serum-free culture conditions by CTG. The concentration of compound that inhibited the cell growth by 50% was determined in those five models (data for Compound 38 is summarized in FIG. 3). Pyrrolopyrimidine Compounds (exemplified by Compound 38) demonstrated potency against mesenchymal GBM CSCs with IC50s in the range of 1-2 μM. This data also indicated that Pyrrolopyrimdine Compounds (as shown for Compound 38) were particularly potent against two GBM CSC sphere models derived from proneural subtype GBM patients with IC50 in the range of 50-190 nM.
TABLE 7
Characteristics of GBM-Cancer Stem Cells
Patient CSCs Clinical Diagnosis Subtype
8311 GBM Mesenchymal (Mes)
52810 GBM Proneural (PN)
81611 GBM PN/Relapse
32612 GBM Mesenchymal (Mes)
1912 GBM Proneural (PN)
Stem Cell Marker Oct-4 Assay.
1200 HUAECs were plated per well of a 384-well plate. After 1 day 8311 GBM CSCs were mechanically-dissociated by trituration and added at a density of 600 cells per well. The cells were allowed to co-culture for 1 day and then treated with various concentrations of Pyrrolopyrimidine Compound or DMSO for 3 days in 5% CO2 at 37° C. After incubation with compound, 40 μL of 4% paraformaldehyde was added. Cell fixation was allowed to proceed at room temperature for 1 hour and each well was washed 5 times with a 50 μL volume of PBS. Each well was treated overnight at 4° C. with a 50 μL volume of PBS supplemented with 3% goat serum and 0.25% triton X-100. Cells were the incubated overnight at 4° C. with anti Oct4 and anti Tuj1 antibodies diluted 1:100 and 1:1000 respectively in PBS/3% goat serum/0.25% triton. Cells were washed 5 times with PBS/0.25% triton and incubated with AlexaFluor-labeled secondary antibodies for 3 hours at room temperature after which the wells were washed 5 times with PBS/0.25% Triton. Images of 4 randomly chosen fields were acquired using an EVOS Cell Imaging System at 10× magnification. Adobe Photoshop (Adobe Systems Incorporated) was used to process raw images, assign and merge channels. Representative images are shown in FIG. 4.
Results.
A defining property of stem cells is their capacity to generate differentiated progeny. GBM CSCs demonstrated the ability to undergo neuronal and astrocytic differentiation upon growth factor withdrawal or following exposure to BMP-4 [Pollard et at Cell Stem Cell 2009; 4(6):568-80]. We evaluated the impact of Pyrrolopyrimidine Compounds on 8311 glioma stem cells in a pathologically relevant GBM-CSC/HUAEC co-culture model. Endothelial cells are known to interact closely with self-renewal GBM-CSC and secret factors maintaining these cells in stem-cell like state [Calabrese et al. Cancer cell 2007; 11(1):69-82]. In this assay, Oct 4 was used as stem cell marker and Tuj-1 was used as neuronal marker for GBM-CSC and differentiated neuronal cell populations, respectively. As shown in FIG. 4, upon Pyrrolopyrimidine Compound treatment (as shown for Compound 38), the Oct4 positive GBM CSC population was decreased while the proportion of Tuj-1 positive neuronal cells was increased. This data indicates that Pyrrolopyrimidine Compounds can eliminate the Oct-4 positive cancer stem cell population and induce neuronal differentiation in the 8311/HUAEC co-culture model.
Conclusions.
Pyrrolopyrimidine Compounds were shown to impair the proliferation of GBM CSC models. Five models isolated from primary GBM patient specimens, representative of mesenchymal and proneural GBM subclasses, were utilized to test Pyrrolopyrimidine Compound activity upon GBM CSCs. Pyrrolopyrimidine Compounds (as exemplified by Compound 38) potently inhibited proliferation of proneural 52810 and 1912 cells with IC50 values of 0.048 and 0.19 μM, respectively. Pyrrolopyrimidine Compounds (exemplified by Compound 38) had less potency in the inhibition of mesenchymal models 8311 and 32612 cells with IC50 values of 1.6 and 1.8 μM, respectively. Furthermore, Pyrrolopyrimidine Compounds (exemplified by Compound 38) induced differentiation of GBM CSCs in the context of a HUAEC co-culture model. Hence, our data indicates that Pyrrolopyrimidine Compounds can both inhibit proliferation and induce neuronal differentiation of GBM CSCs.
ANIMAL MODELS
Cancer Xenograft Model.
For xenograft model studies human cancer cell lines were injected into SCID (severe combined immunodeficiency) mice. Cancer cell lines were propagated in culture in vitro. Tumor bearing animals were generated by injecting precisely determined numbers of cells into mice. Following inoculation of animals, the tumors were allowed to grow to a certain size prior to randomization. The mice bearing xenograft tumors, typically ranging between 100 and 400 mm3, were pooled together and randomized into various treatment groups. Primary tumorgrafts were propagated in vivo. Tumor fragments from donor mice were implanted into small numbers of mice for maintenance, or larger numbers of mice for study initiation. A typical efficacy study design involved administering one or more compounds at various dose levels to tumor-bearing mice. Additionally, reference chemotherapeutic agents (positive control) and negative controls were similarly administered and maintained. Routes of administration can include subcutaneous (SC), intraperitoneal (IP), intravenous (IV), intramuscular (IM) and oral (PO). Tumor measurements and body weights were taken over the course of the study and morbidity and mortality were recorded. Necropsy, histopathology, and PCR can also be performed to enhance understanding of disease and drug action.
Some of the typical human bladder cancer cell lines, for example transitional cell carcinoma, that were or can be used in the above xenograft models are: HT-1376, HT-1197, UMUC-3, KU-7, and KU-19-19 cell lines.
Some of the typical human breast cancer cell lines that were or can be used in the above xenograft models are: luminal-B type cell lines, for example BT-474, or ZR-75, and basal type cell lines, for example, MDA-MB-231, T47D, and Cal-51 cell lines.
Some of the typical human lung squamous cell carcinoma cell lines, that were or can be used in the above xenograft models are: SK-MES-1, NCI-H1703, HCC-15, and Calu-1 cell line.
Some of the typical human esophageal squamous carcinoma cell lines that were or can be used in the above xenograft models are: Kyse-140 and KYSE-510 cell lines.
Some of the typical human squamous cervical cancer cell lines that were or can be used in the above xenograft models are: A-431 and SiHa cell lines.
Some of the typical human squamous head and neck cancer cell lines that were or can be used in the above xenograft models are: FaDu and SCC-15 cell lines.
Some of the typical human leukemia cell lines that were or can be used in the above xenograft models are: CCRF-CEM and MOLT-4.
Some of the typical human lymphoma cell lines that were or can be used in the above xenograft models are: WSU-DLCL2 and OCI-Ly10.
Some of the typical human colorectal cancer (CRC) cell lines that were or can be used in the above xenograft models are: HCT-116, HT-29, and LOVO.
Some of the typical human thyroid cancer cell lines that were or can be used in the above xenograft models are: TT and 8305C.
Some of the typical human central nervous system (CNS) cancer cell lines that were or can be used in the above xenograft models are: U87MG and U-118.
Some of the typical human pancreas cancer cell lines that were or can be used in the above xenograft models are: PANC-1 and BxPC3.
For a typical xenograft study, SCID mice bearing tumors were randomized and dosed with compounds ranging from, for example, 100 mg/kg to 0.1 mg/kg with different dose scheduling. The mice were dosed for 2-4 weeks. Tumors were measured twice a week using calipers and tumor volumes were calculated using the formula of W2×L/2.
In thesexenograft cancer models, Pyrrolopyrimidine Compounds have, or are expected to have, an ED50 value of <100 mg/kg, with some compounds having an ED50 of <10 mg/kg and others an ED50 of <1 mg/kg.
A number of references have been cited, the disclosures of which are incorporated herein by reference in their entirety.

Claims (18)

What is claimed is:
1. A method for treating glioblastoma multiforme, comprising administering to a subject having glioblastoma multiforme an effective amount of Pyrrolopyrimidine Compound, wherein the Pyrrolopyrimidine Compound is a compound of formula (I):
Figure US09623028-20170418-C00454
and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, and isotopologues thereof,
wherein:
R1 is substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclyl;
R2 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl, and
L is NH or O;
provided
R3 is not pyridyl when L is NH or when R2 is pyrazolyl; and
the compound is not
N-methyl-N-[trans-3-[[5-(1-methyl-1H-pyrazol-4-yl)-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]cyclobutyl]-2-propenamide; or
N-methyl-N-[trans-3-[[5-(1-methyl-1H-pyrazol-3-yl)-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]cyclobutyl]-2-propenamide.
2. The method of claim 1, wherein L is O.
3. The method of claim 1, wherein R1 is substituted or unsubstituted C3-8 cycloalkyl.
4. The method of claim 1, wherein R1 is substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
5. The method of claim 3, wherein the cycloalkyl is substituted with one or more —CN, halogen, —OR or a substituted or unsubstituted C1-3 alkyl, wherein each R is independently —H or substituted or unsubstituted (C1-4)alkyl.
6. The method of claim 1, wherein R1 is substituted or unsubstituted C1-8 alkyl,
Figure US09623028-20170418-C00455
wherein
each R′ is independently —CN, halogen, —OR or C1-3 alkyl;
R″ is —H or C1-3 alkyl;
each R is independently H or substituted or unsubstituted (C1-4)alkyl; and
n is 0-2.
7. The method of claim 1, wherein R2 is substituted phenyl.
8. The method of claim 7, wherein R2 is phenyl, substituted with one or more substituted or unsubstituted C1-6 alkyl, halogen, —CN, —OR5, —C(═O)NR5 2, —C(═O) (substituted or unsubstituted heterocyclyl), —C(═O) (substituted or unsubstituted alkylheterocyclyl), —NHC(═O)R5, —SO2NR5 2, or substituted or unsubstituted heteroaryl, wherein each R5 is independently —H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkylheterocyclyl.
9. The method of claim 7, wherein R2 is phenyl, substituted with one or more —(C1-3 alkyl), —(C1-3 alkyl)NR2, —CF3, —Cl, —F, —CN, —OCH3, —OCF3, —C(═O)NR2, —C(═O)NR (substituted or unsubstituted cycloalkyl), —C(═O)NR(CH2)0-2CR2(CH2)0-2OR, —C(═O)NR(CH2)0-2CR2(CH2)0-2NR2, —C(═O)NR(CH2)0-2CR2(CH2)0-2C(═O)NR2, —C(═O)N (substituted or unsubstituted cycloalkyl)(CH2)0-2OR, —C(═O)NR(CH2)0-3 (substituted or unsubstituted heterocyclyl), —C(═O)(CH2)0-3 (substituted or unsubstituted heterocyclyl), —C(═NR)NR2, —NRC(═O)R, —SO2NR2, —SO2R, or substituted or unsubstituted heterocyclyl, wherein each R is independently —H or substituted or unsubstituted (C1-4)alkyl.
10. The method of claim 9, wherein each R is independently —H or —CH3.
11. The method of claim 7, wherein R2 is phenyl, substituted with one or more —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —CH2NH2, —CF3, —Cl, —F, —CN, —OCH3, —OCF3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, —C(═O)NC(CH3)3, —C(═O)NHCH2CH2F, —C(═O)NHCH2CHF2, —C(═O)NHCH2CF3, —C(═O)NHCH2CF2CH3, —C(═O)NHCH2CN, —C(═O)N(CH3)CH2CN, —C(═O)NHCH2CH2CN, —C(═O)N(CH3)CH2CH2CN, —C(═O)NH-cyclobutyl, —C(═O)NH-(hydroxy-cyclobutyl), —C(═O)NH-cyclopentyl, —C(═O)NH-(hydroxy-cyclopentyl), —C(═O)NHCH2CH2OH, —C(═O)NHCH2CH2OCH3, —C(═O)N(CH3)CH2CH2OH, —C(═O)N(CH3)CH2CH2OCH3, —C(═O)NHCH2CH2CH2OH, —C(═O)N(CH3)CH2CH2CH2OH, —C(═O)N(CH3)CH2CH2CH2OCH3, —C(═O)NHCH2CH(CH3)OH, —C(═O)NHCH2C(CH3)2OH, —C(═O)NHCH(CH3)CH2OH, —C(═O)NHC(CH3)2CH2OH, —C(═O)NHCH2CH2NH2, —C(═O)NHCH2CH2NH(CH3), —C(═O)NHCH2CH2N(CH3)2, —C(═O)NHCH2C(═O)NH2, —C(═O)N(CH3)CH2C(═O)NH2, —C(═O)NHCH2CH2C(═O)NH2, —C(═O)N(CH3)CH2CH2C(═O)NH2, —C(═O)N(cyclopropyl)CH2CH2OH, —C(═O)NH-oxetanyl, —C(═O)N(CH3)-oxetanyl, —C(═O)NH-(methyl-oxetanyl), —C(═O)NH-azetidinyl, —C(═O)NH-(methylazetidinyl), —C(═O)NH-(1-acetylazetidinyl), —C(═O)NH-pyrrolidyl, —C(═O)NH-piperidyl, —C(═O)NH-tetrahydrofuranyl, —C(═O)N(CH3)-tetrahydrofuranyl, —C(═O)NH-tetrahydropyranyl, —C(═O)N(CH3)-tetrahydropyranyl, —C(═O)NHCH2-oxetanyl, —C(═O)N(CH3)CH2-oxetanyl, —C(═O)NHCH2-(methyl-oxetanyl), —C(═O)N(CH3)CH2-(methyl-oxetanyl), —C(═O)NHCH2-tetrahydrofuranyl, —C(═O)NHCH2-tetrahydropyranyl, —C(═O)NHCH2-dioxanyl, —C(═O)aziridinyl, —C(═O)(methyl-aziridinyl), —C(═O)(dimethyl-aziridinyl), —C(═O)(hydroxymethyl-aziridinyl), —C(═O)azetidinyl, —C(═O)pyrrolidinyl, —C(═O)(hydroxyl-pyrrolidinyl), —C(═O)(hydroxyl, methoxypyrrolidinyl), —C(═O)(dimethoxypyrrolidinyl), —C(═O)morpholinyl, —C(═O)piperazinyl, —C(═O)(methylpiperazinyl), —C(═O)(hydroxy-piperidyl), —C(═O)(fluoropiperidinyl), —(C═O)(methoxy-piperidyl), —C(═NH)NH2, —NHC(═O)CH3, —SO2NHCH3, —SO2CH3, or substituted or unsubstituted pyrazolyl.
12. The method of claim 7, wherein R2 is phenyl, substituted with one or more —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —CH2NH2, —CF3, —F, —CN, —OCH3, —OCF3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, —C(═O)NC(CH3)3, —C(═O)NHCH2CH2F, —C(═O)NHCH2CF2CH3, —C(═O)N(CH3)CH2CN, —C(═O)N(CH3)CH2CH2CN, —C(═O)NH-(3-hydroxy-cyclobutyl), —C(═O)NH-cyclopentyl, —C(═O)NH-(2-hydroxycyclopentyl), —C(═O)NHCH2CH2OH, —C(═O)NHCH2CH2OCH3, —C(═O)N(CH3)CH2CH2OH, —C(═O)N(CH3)CH2CH2OCH3, —C(═O)NHCH2CH2CH2OH, —C(═O)N(CH3)CH2CH2CH2OH, —C(═O)NHCH2CH(CH3)OH, —C(═O)NHCH2C(CH3)2OH, —C(═O)NHCH(CH3)CH2OH, —C(═O)NHC(CH3)2CH2OH, —C(═O)NHCH2CH2NH2, —C(═O)NHCH2CH2NH(CH3), —C(═O)NHCH2CH2N(CH3)2, —C(═O)N(CH3)CH2C(═O)NH2, —C(═O)N(CH3)CH2CH2C(═O)NH2, —C(═O)N(cyclopropyl)CH2CH2OH, —C(═O)NH-oxetanyl, —C(═O)N(CH3)-oxetanyl, —C(═O)NH-(3-methyl-oxetanyl), —C(═O)NH-(1-methylazetidinyl), —C(═O)NH-(1-acetylazetidinyl), —C(═O)NH-piperidyl, —C(═O)NH-tetrahydrofuranyl, —C(═O)NH-tetrahydropyranyl, —C(═O)N(CH3)-tetrahydropyranyl, —C(═O)NHCH2-oxetanyl, —C(═O)N(CH3)CH2-(3-methyl-oxetanyl), —C(═O)NHCH2-tetrahydrofuranyl, —C(═O)NHCH2-tetrahydropyranyl, —C(═O)NHCH2-dioxanyl, —C(═O)aziridinyl, —C(═O)(2-methyl-aziridinyl), —C(═O)(2,2-dimethyl-aziridinyl), —C(═O)(2-(hydroxymethyl)aziridinyl), —C(═O)azetidinyl, —C(═O)pyrrolidinyl, —C(═O)(3-hydroxy-4-methoxypyrrolidinyl), —C(═O)(3,4-dimethoxypyrrolidinyl), —C(═O)morpholinyl, —C(═O)piperazinyl, —C(═O)(4-methylpiperazinyl), —C(═O)(4-hydroxy-piperidyl), —C(═O)(4,4-difluoropiperidinyl), —(C═O)(4-methoxy-piperidyl), —C(═NH)NH2, —NHC(═O)CH3, —SO2NHCH3, —SO2CH3, or substituted or unsubstituted pyrazolyl.
13. The method of claim 1, wherein R3 is substituted or unsubstituted heterocyclyl.
14. The method of claim 13, wherein the heterocyclyl is substituted or unsubstituted pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, benztriazolyl, indazolyl, indolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzoxazolonyl, benzoxadiazolyl, benzimidazolyl, or quinolyl.
15. The method of claim 13, wherein the heterocyclyl is substituted with one or more substituents selected from substituted or unsubstituted (C1-4)alkyl, halogen, —OR, —CN, —NR2, —C(═O)NR2, —NRC(═O)R, or substituted or unsubstituted triazolyl, wherein each R is independently H or substituted or unsubstituted (C1-4)alkyl.
16. The method of claim 13, wherein the heterocyclyl is substituted with one or more substituents selected from —CH3, —CH(CH3)2, —F, —Cl, —OH, —OCH3, —OCH2CH3, —CN, —NH2, —NHCH3, —N(CH3)2, —C(═O)NH(CH3), —NHC(═O)CH3, or substituted or unsubstituted triazolyl.
17. The method of claim 1, wherein R3 is substituted or unsubstituted aryl.
18. The method of claim 1, wherein the compound is selected from
4-(4-(cyclopentyloxy)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(3-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(4-hydroxyphenyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
4-(2-(1H-indazol-5-ylamino)-4-(cyclohexyloxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol,
4-(2-(4-(1H-pyrazol-4-yl)phenylamino)-4-(cyclohexyloxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol,
4-(5-(2-chloro-4-hydroxyphenyl)-4-(cyclohexyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
4-(2-(3-(1H-pyrazol-4-yl)phenylamino)-4-(cyclohexyloxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol,
4-(4-(cyclopentyloxy)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,3-dimethylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-ethyl-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-isopropyl-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-chloro-4-(4-(cyclopentyloxy)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-fluoro-N-methylbenzamide,
4-(4-(cyclopentylamino)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(4-hydroxyphenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(4-hydroxyphenyl)-4-(neopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(4-hydroxyphenyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-2-(1-methyl-1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol,
4-(4-(cyclopentyloxy)-2-(6-methyl-1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol,
4-(4-(cyclopentyloxy)-2-(4-methyl-1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol,
4-(4-(cyclopentyloxy)-5-(4-(hydroxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(3-chloro-4-hydroxyphenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(1H-indazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(3-(hydroxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(1H-benzo[d][1,2,3]triazol-6-yl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-chloro-4-(5-(4-hydroxyphenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
4-(5-(1H-benzo[d]imidazol-6-yl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N,N-dimethylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-(methylsulfonamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(3-cyano-4-hydroxyphenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-chloro-4-(4-(cyclopentyloxy)-5-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclohexylamino)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(4-aminophenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-ureidophenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(4-hydroxyphenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(4-(1H-pyrazol-5-yl)phenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(3-fluoro-4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-hydroxy-3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxybenzamide,
4-(4-((1r,4r)-4-hydroxycyclohexyloxy)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-((1s,4s)-4-hydroxycyclohexyloxy)-5-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(3-(2-hydroxypropan-2-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(4-(1H-imidazol-2-yl)phenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-(2-hydroxypropan-2-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-2-(2-methoxy-4-(1H-pyrazol-4-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol,
4-(4-(cyclopentyloxy)-5-(5-hydroxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(2-(4-(aminomethyl)-2-methoxyphenylamino)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol,
4-(5-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-chloro-N,N-dimethylbenzamide,
4-(4-(cyclopentyloxy)-5-(3-fluoro-4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(3-acetamidophenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(3-(methylsulfonamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(3-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(4-acetamidophenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(3-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(3,4-dimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(3-aminophenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(6-ethoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
(4-(5-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-chlorophenyl)(morpholino)-methanone,
N,N,3-trimethyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
N,N,3-trimethyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(5-(2-amino-1H-benzo[d]imidazol-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-chloro-N,N-dimethylbenzamide,
4-(5-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-chloro-N,N-dimethylbenzamide,
4-(4-methoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
(3-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)(piperazin-1-yl)methanone,
4-(4-(cyclopentyloxy)-5-(4-(dimethylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(4-cyanophenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(1-methyl-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-chloro-4-(4-methoxy-5-(2-methyl-1H-benzo[d]imidazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N-dimethylbenzamide,
(R)-3-chloro-4-(5-(3-(1-hydroxyethyl)phenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N-dimethylbenzamide,
(S)-3-chloro-4-(5-(3-(1-hydroxyethyl)phenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N-dimethylbenzamide,
(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methylphenyl)(morpholino)methanone,
N-(1H-indazol-5-yl)-4-methoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
N-(4-(1H-pyrazol-4-yl)phenyl)-4-methoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
4-(4-methoxy-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
3-methoxy-N-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N,N-dimethylbenzamide,
4-(4-((1r,4r)-4-hydroxycyclohexyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
N,N,3-trimethyl-4-(5-(pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,3-dimethylbenzamide,
N,N,3-trimethyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(1-methylpiperidin-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)(morpholino)methanone,
N,N,3-trimethyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(piperidin-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(S)-N,N,3-trimethyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(R)-N,N,3-trimethyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
N-(2-aminoethyl)-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxybenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(2-hydroxyethyl)-3-methoxybenzamide,
4-(5-(6-ethoxypyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(cyclopentyloxy)-N-(2-methoxyphenyl)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
(S)-N,N,3-trimethyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
N,N,3-trimethyl-4-(5-(3-(methyl sulfonyl)phenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-N-methyl-4-(5-(3-(methylsulfonyl)phenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
N,N,3-trimethyl-4-(5-(pyrimidin-5-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-N-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(5-(6-ethoxypyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N, 3-trimethylbenzamide,
4-(5-(2-amino-1H-benzo[d]imidazol-6-yl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(1,3,4-oxadiazol-2-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N, 3-trimethylbenzamide,
N,N,3-trimethyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
N,N,3-trimethyl-4-(5-(1-methyl-1H-pyrazol-3-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-N-methyl-4-(5-(pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
N,N,3-trimethyl-4-(5-(oxazol-2-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(5-(2-amino-1H-benzo[d]imidazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
N,N,3-trimethyl-4-(5-(2-methylpyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-4-(4-methoxy-5-(6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
3-methoxy-4-(5-(6-methoxypyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
3-methoxy-N-(2-methoxyethyl)-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(R)-N,N,3-trimethyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(5-(1H-pyrazol-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-methoxy-N-methyl-4-(5-(4-(methylcarbamoyl)phenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-4-(4-methoxy-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
4-(4-isopropoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(6-(dimethylamino)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
N-(2-(dimethylamino)ethyl)-3-methoxy-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
N,N,3-trimethyl-4-(5-(2-methyl-1H-benzo[d]imidazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-4-(4-methoxy-5-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
3-methoxy-N-(2-(methylamino)ethyl)-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(5-(2-(dimethylamino)pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-chloro-N-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(S)-N,3-dimethyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(S)-3-chloro-N-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(5-(2,7-dimethylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(2,5-dimethylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-((1r,4r-4-hydroxycyclohexyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-methoxy-N-methyl-4-(4-(2-(methylamino)ethoxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-4-(4-(2-methoxyethoxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
4-(5-(2-cyanopyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
4-(5-(4-(1H-imidazol-2-yl)phenyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(2-aminopyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-methoxy-4-(5-(2-methoxypyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
N,3-dimethyl-4-(5-(3-(methylcarbamoyl)phenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
N,3-dimethyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(5-(4-(1H-imidazol-2-yl)phenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(2-hydroxypyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(1,2-dimethyl-1H-benzo[d]imidazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-methoxy-5-(3-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,3-dimethylbenzamide,
4-(4-((1r,4r-4-hydroxy-4-methylcyclohexyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,3-dimethylbenzamide,
4-(4-((1s,4s)-4-hydroxy-4-methylcyclohexyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,3-dimethylbenzamide,
4-(4-cyclopropoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
(S)-N,3-dimethyl-4-(5-(4-(methylcarbamoyl)phenyl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-N-methyl-4-(5-(pyrimidin-5-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-N-methyl-4-(5-(2-(methylamino)pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(4-methoxy-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,3-dimethylbenzamide,
3-chloro-4-(4-methoxy-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N-dimethylbenzamide,
N,3-dimethyl-4-(5-(4-(methyl sulfonyl)phenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
5-(2-(4-(dimethylcarbamoyl)-2-methylphenylamino)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylpicolinamide,
N-(2-hydroxyethyl)-4-(4-isopropoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxybenzamide,
(S)-4-(5-(6-ethoxypyridin-3-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
(S)-4-(5-(6-ethoxypyridin-3-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,3-dimethylbenzamide,
3-methoxy-N-methyl-4-(5-(1-methyl-1H-pyrazol-3-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(S)-N,N,3-trimethyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(S)-N,3-dimethyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-4-(4-methoxy-5-(2-methylpyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
3-methoxy-N-methyl-4-(5-(2-methylpyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(4-(2-hydroxyethoxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
(S)-3-methoxy-N-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(5-(2-isopropylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-cyano-N-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-N-methyl-4-(5-(1-methyl-1H-imidazol-2-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-N-methyl-4-(5-(oxazol-2-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(5-(1,3,4-oxadiazol-2-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
(S)-4-(5-(3-(1-hydroxyethyl)phenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
(S)-N,N,3-trimethyl-4-(5-(pyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-4-(4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
(S)-3-methoxy-N-methyl-4-(5-(2-methylpyridin-4-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-N-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(oxetan-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-(4-isopropoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-4-methoxy-N-methylbenzamide,
4-methoxy-N-methyl-3-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(S)-3-methoxy-N-methyl-4-(5-(4-(methylcarbamoyl)phenyl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
6-methoxy-N-methyl-5-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)picolinamide,
3-methoxy-N-methyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(4-isopropoxy-5-(2-methoxypyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-methoxy-N-methyl-4-(5-(pyrazin-2-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(4-isopropoxy-5-(3-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-isopropoxy-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-isopropoxy-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-methoxy-4-(4-methoxy-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
N-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-(trifluoromethyl)benzamide,
N-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-(trifluoromethoxy)benzamide,
4-(5-(4-(1H-imidazol-2-yl)phenyl)-4-isopropoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(2-aminopyridin-4-yl)-4-isopropoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-methoxy-N-methyl-4-(5-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(5-(6-ethoxypyridin-3-yl)-4-isopropoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(4-(4, 5-dimethyl-1H-imidazol-2-yl)phenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-cyclobutoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-isopropoxy-5-(2-(methylamino)pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-isopropyl-N-methyl-4-(5-(pyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(4-isopropoxy-5-(2-methylpyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(isopropylamino)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
(R)-4-(4-sec-butoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
(S)-4-(4-sec-butoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-((1r,4r-4-hydroxy-4-methylcyclohexyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-((1s,4s)-4-hydroxy-4-methylcyclohexyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-methoxy-N-methyl-4-(5-(4-(4-methyl-1H-imidazol-2-yl)phenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(S)-3-isopropyl-N-methyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(S)-3-isopropyl-N-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-N-methyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-4-(tetrahydro-2H-pyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(4-(cyclopropylamino)-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopropylamino)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
N-(2-hydroxyethyl)-3-methoxy-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(R)-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(1-hydroxypropan-2-yl)-3-methoxybenzamide,
(S)-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(1-hydroxypropan-2-yl)-3-methoxybenzamide,
4-(4-cyclopropoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(2-hydroxyethyl)-3-methoxybenzamide,
4-(4-cyclopropoxy-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(2-hydroxyethyl)-3-methoxybenzamide,
4-(4-cyclopropoxy-5-(1-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-methoxy-N-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzenesulfonamide,
4-(4-isopropoxy-5-(1-methyl-1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-methoxy-4-(4-(2-methoxyethoxy)-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N-dimethylbenzamide,
(R)-3-methoxy-N,N-dimethyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-N-methyl-4-(5-(2-methylbenzo[d]thiazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
N-tert-butyl-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxybenzamide,
(S)-3-isopropyl-N-methyl-4-(5-(1-methyl-1H-pyrazol-5-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(4-isopropoxy-5-(1-methyl-1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(cyclopentyloxy)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
4-(cyclopentyloxy)-N-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
N-cyclopentyl-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxybenzamide,
(R)-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(2-hydroxypropyl)-3-methoxybenzamide,
(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)(4-hydroxypiperidin-1-yl)methanone,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(3-hydroxypropyl)-3-methoxybenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(2-hydroxyethyl)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(1-hydroxy-2-methylpropan-2-yl)-3-methoxybenzamide,
5-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)isoindolin-1-one,
4-(5-(2-acetamidopyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-2-fluoro-5-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-((1s,3s)-3-hydroxycyclobutyl)-3-methoxybenzamide, 4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-((1r,3r)-3-hydroxycyclobutyl)-3-methoxybenzamide,
(S)-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(2-hydroxypropyl)-3-methoxybenzamide,
azetidin-1-yl(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)methanone,
(R)-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-((tetrahydrofuran-2-yl)methyl)benzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide,
5-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-2-methylisoindolin-1-one,
4-(5-(4-carbamimidoylphenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-tert-butoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
N-(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)acetamide,
N-(2-cyanoethyl)-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)(pyrrolidin-1-yl)methanone,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-cyclopropyl-N-(2-hydroxyethyl)-3-methoxybenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)benzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-((1R,2S)-2-hydroxycyclopentyl)-3-methoxybenzamide,
(S)-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-((tetrahydrofuran-2-yl)methyl)benzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(2-fluoroethyl)-3-methoxybenzamide,
N-(3-amino-3-oxopropyl)-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(2-hydroxyethyl)-3-methoxybenzamide,
(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone,
4-(5-(benzo[c][1,2,5]oxadiazol-5-yl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(cyclopentyloxy)-N-(5-fluoro-2-methoxy-4-(methylsulfonyl)phenyl)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
aziridin-1-yl(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)methanone,
N-(cyanomethyl)-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-((1S,2R)-2-hydroxycyclopentyl)-3-methoxybenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-((1S,2S)-2-hydroxycyclopentyl)-3-methoxybenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-((1R,2R)-2-hydroxycyclopentyl)-3-methoxybenzamide,
(S)-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(tetrahydrofuran-3-yl)benzamide,
N-(2-amino-2-oxoethyl)-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-methoxy-N-methyl-4-(5-(pyridazin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-N-methyl-4-(5-(pyrimidin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methyl-N-((3-methyloxetan-3-yl)methyl)benzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methyl-N-(oxetan-3-yl)benzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(tetrahydro-2H-pyran-3-yl)benzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(tetrahydro-2H-pyran-3-yl)benzamide,
(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)(4-methoxypiperidin-1-yl)methanone,
(S)-4-(4-sec-butoxy-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxybenzonitrile,
4-(4-(cyclopentyloxy)-5-(1-methyl-1H-indazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(3-methylbenzo[d]isoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
5-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-4-methoxy-N-methylpicolinamide,
N-((1,4-dioxan-2-yl)methyl)-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxybenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-ylmethyl)benzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(3-hydroxypropyl)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(2-methoxyethyl)-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(2-hydroxy-2-methylpropyl)-3-methoxybenzamide,
(S)-4-(4-sec-butoxy-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(2-hydroxyethyl)-3-methoxybenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxybenzimidamide,
4-(2-(2-methoxy-4-(methylcarbamoyl)phenylamino)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylpicolinamide,
(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)(4,4-difluoropiperidin-1-yl)methanone,
4-(5-(4-acetamido-3-hydroxyphenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)((3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl)methanone,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(piperidin-1-yl)benzamide,
4-(4-(cyclopentyloxy)-5-(2-ethoxybenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(5-(4-amino-3-hydroxyphenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(cyclopentyloxy)-N-(1-methyl-1H-pyrazol-5-yl)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
4-(cyclopentyloxy)-N-(1,5-dimethyl-1H-pyrazol-4-yl)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
4-(cyclopentyloxy)-N-(1,4-dimethyl-1H-pyrazol-3-yl)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N, 5-dimethylbenzamide,
4-(4-(cyclopentyloxy)-5-(2-oxo-2, 3-dihydrobenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(3-methyloxetan-3-yl)benzamide,
4-(4-cyclobutoxy-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
4-(4-(cyclopentyloxy)-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
4-(4-cyclobutoxy-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
4-(4-(cyclopentyloxy)-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
4-(4-(cyclopentyloxy)-5-(quinolin-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(cyclopentyloxy)-N-(1,3-dimethyl-1H-pyrazol-4-yl)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
N-(1-acetylazetidin-3-yl)-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxybenzamide,
4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(2,2-difluoropropyl)-3-methoxybenzamide,
3-methoxy-4-(5-(4-(methylcarbamoyl)phenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)((3R,4R)-3,4-dimethoxypyrrolidin-1-yl)methanone,
(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)(2,2-dimethylaziridin-1-yl)methanone,
(S)-(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)(2-methylaziridin-1-yl)methanone,
4-(4-((1s,4s)-4-hydroxy-4-methylcyclohexyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
aziridin-1-yl(4-(4-((1s,4s)-4-hydroxy-4-methylcyclohexyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)methanone,
4-(4-(cyclopentyloxy)-2-(1-methyl-1H-pyrazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide,
N-methyl-4-(2-(1-methyl-1H-pyrazol-5-ylamino)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzamide,
methyl 4-(4-(cyclopentyloxy)-2-(2-methoxy-4-(methylcarbamoyl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzoate,
4-(4-(cyclopentyloxy)-5-(4-fluoro-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(2,4-dimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(3,5-dimethylisoxazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(3-(dimethylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-(cyclopentyloxy)-5-(3-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide, 4-(5-(3-cyanophenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
3-methoxy-4-(5-(5-methoxypyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
3-methoxy-4-(4-(2-methoxyethoxy)-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
N-(2-hydroxyethyl)-3-methoxy-4-(5-(1-methyl-1H-pyrazol-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(S)-3-methoxy-N-methyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
N-methyl-4-(2-(1-methyl-1H-pyrazol-5-ylamino)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzamide,
4-(4-(cyclopentyloxy)-5-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methylbenzamide,
4-(4-cyclobutoxy-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(2-hydroxyethyl)-3-methoxybenzamide,
4-(4-cyclobutoxy-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methyl-N-(oxetan-3-yl)benzamide,
3-chloro-4-(4-cyclobutoxy-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
4-(4-isopropoxy-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
(R)-(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)(2-methylaziridin-1-yl)methanone,
4-(2-(4-(aziridine-1-carbonyl)-2-methoxyphenylamino)-4-((1s,4s)-4-hydroxy-4-methylcyclohexyloxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide,
4-(4-((1s,4s)-4-hydroxy-4-methylcyclohexyloxy)-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
aziridin-1-yl(3-methoxy-4-(4-methoxy-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)methanone,
4-(4-cyclobutoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
4-(4-cyclobutoxy-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide,
4-(4-(3-cyanocyclobutoxy)-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
4-(2-(5-chloro-1-methyl-1H-pyrazol-4-ylamino)-4-cyclobutoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide,
(S)-3-methoxy-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
4-(4-cyclopropoxy-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
4-(4-(3,3-difluorocyclobutoxy)-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
(R)-(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)(2-(hydroxymethyl)aziridin-1-yl)methanone,
3-methoxy-4-(4-methoxy-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
4-(4-cyclobutoxy-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide,
4-(4-((1s,4s)-4-hydroxy-4-methylcyclohexyloxy)-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide,
(S)-(4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxyphenyl)(2-(hydroxymethyl)aziridin-1-yl)methanone,
N-(5-chloro-1-isopropyl-1H-pyrazol-4-yl)-4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
5-(4-cyclobutoxy-2-(2-methoxy-4-(oxetan-3-ylcarbamoyl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylpicolinamide,
4-(4-cyclobutoxy-2-(2-methoxy-4-(oxetan-3-ylcarbamoyl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-N-methylbenzamide,
4-(4-tert-butoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide,
4-(4-tert-butoxy-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide,
4-(4-isopropoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide,
4-(4-isopropoxy-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide,
4-(4-((1s,4s)-4-hydroxy-4-methylcyclohexyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide,
3-methoxy-4-(5-(4-(methylcarbamoyl)phenyl)-4-(oxetan-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
4-(5-(4-(1H-imidazol-2-yl)phenyl)-4-cyclobutoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
4-(5-(4-(1H-imidazol-2-yl)phenyl)-4-(cyclopentyloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide,
4-(4-isopropoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
4-(4-cyclopropoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide,
4-(4-cyclopropoxy-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide,
3-methoxy-4-(4-(2-methoxyethoxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
3-methoxy-N-(1-methylazetidin-3-yl)-4-(5-(4-(methylcarbamoyl)phenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-N-(1-methylazetidin-3-yl)-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-methoxy-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
4-(4-cyclopropoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
4-(4-tert-butoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
1-(5-chloro-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol,
4-(2-(5-chloro-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-ylamino)-4-cyclobutoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide,
3-methoxy-4-(4-(2-methoxyethoxy)-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
(S)-3-methoxy-N-(1-methylazetidin-3-yl)-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(S)-3-methoxy-N-(1-methylazetidin-3-yl)-4-(5-(4-(methylcarbamoyl)phenyl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(S)-3-methoxy-4-(5-(4-(methylcarbamoyl)phenyl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
N-(5-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
N-(5-chloro-1-(2-methoxyethyl)-1H-pyrazol-4-yl)-4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
3-methoxy-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(1-methylcyclobutoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
3-methoxy-4-(4-methoxy-5-(3-methylbenzo[d]isoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
4-(5-(2-fluoropyridin-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
3-methoxy-4-(4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
3-methoxy-4-(4-methoxy-5-(2-methylpyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
4-(5-(2,6-dimethylpyridin-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
N-(5-chloro-1-ethyl-1H-pyrazol-4-yl)-4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
3-methoxy-4-(4-(2-methoxyethoxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(1-methylazetidin-3-yl)benzamide,
4-(5-(1,3-dimethyl-1H-pyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
3-methoxy-4-(4-methoxy-5-(3-methylbenzo[d]isoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
3-methoxy-4-(4-methoxy-5-(2-methoxypyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
4-(5-(4-fluorophenyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
4-(4-methoxy-5-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
3-methoxy-4-(4-methoxy-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N-dimethylbenzamide,
N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-methoxy-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
4-(5-(2-chloropyridin-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
3-methoxy-4-(4-methoxy-5-(pyrimidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
4-(4-methoxy-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methyl-N-(oxetan-3-yl)benzamide,
4-(5-(4-(1H-imidazol-2-yl)phenyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
4-(4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
4-(4-methoxy-5-(2-methyl-1H-benzo[d]imidazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
4-(4-methoxy-5-(3-methylbenzo[d]isoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
4-methoxy-N-(1-methyl-1H-pyrazol-5-yl)-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
4-(5-(2-fluoropyridin-4-yl)-4-isopropoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
4-(5-(2-fluoropyridin-4-yl)-4-isopropoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N,N-dimethylbenzamide,
3-methoxy-4-(4-methoxy-5-(2-methyl-1H-benzo[d]imidazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
3-methoxy-4-(4-methoxy-5-(pyridazin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
4-(4-methoxy-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,3-dimethyl-N-(oxetan-3-yl)benzamide,
4-(5-(1,2-dimethyl-1H-benzo[d]imidazol-6-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
3-methoxy-4-(4-methoxy-5-(3-methylbenzo[d]isoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N-dimethylbenzamide,
4-(5-(2-fluoropyridin-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
4-(5-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
4-(4-methoxy-5-(4-(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
4-(5-(2-fluoropyridin-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N,N-dimethylbenzamide,
4-(5-(2-fluoropyridin-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-methyl-N-(oxetan-3-yl)benzamide,
4-methoxy-N-(4-methyl-1H-indazol-5-yl)-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
5-(5-(2-fluoropyridin-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-4-methoxy-N,N-dimethylpicolinamide,
5-(2-fluoropyridin-4-yl)-4-methoxy-N-(4-methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,
4-(5-(3-chloro-1-methyl-1H-pyrazol-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
4-(5-(2-fluoro-6-methylpyridin-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N,N-dimethylbenzamide,
N-(1,4-dimethyl-1H-indazol-5-yl)-4-methoxy-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine
4-(5-(2-fluoro-6-methylpyridin-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N,3-trimethylbenzamide,
3-chloro-N-methyl-4-(5-(4-(methylcarbamoyl)phenyl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-chloro-4-(4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
3-chloro-N-methyl-4-(5-(1-methyl-1H-pyrazol-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
4-(5-(2-fluoro-6-methylpyridin-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
3-chloro-4-(4-(cyclopentyloxy)-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
3-chloro-4-(4-isopropoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
3-chloro-4-(4-methoxy-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
3-chloro-4-(4-methoxy-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
3-chloro-4-(4-((1s,4s)-4-hydroxy-4-methylcyclohexyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
3-chloro-N-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-chloro-N-(2-hydroxyethyl)-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-chloro-4-(4-isopropoxy-5-(4-(methylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-methylbenzamide,
3-chloro-N-methyl-4-(5-(4-(methylcarbamoyl)phenyl)-4-(tetrahydro-2H-pyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
(R)-3-chloro-N-methyl-4-(5-(4-(methylcarbamoyl)phenyl)-4-(tetrahydrofuran-3-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
3-ethyl-N-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide,
N-methyl-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-propylbenzamide,
4-(5-(2-chloro-6-methylpyridin-4-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-3-methoxy-N-(oxetan-3-yl)benzamide,
3-chloro-4-(5-(2-methylbenzo[d]oxazol-6-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N-(oxetan-3-yl)benzamide,
or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, or isotopologue thereof.
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